Eif4a-inhibiting compounds and methods related thereto

ABSTRACT

The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. 
     
       
         
         
             
             
         
       
     
     For Formula I compounds X, Y, R 1 , R 2 , R 3a , R 3b , R 4a , R 4b  and R 5  are as defined in the specification. The inventive Formula I compounds are inhibitors of eIF4A and find utility in any number of therapeutic applications, including but not limited to treatment of inflammation and various cancers.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

The present application claims the benefit of U.S. provisionalapplication No. 62/259,828, filed Nov. 25, 2015, and U.S. provisionalapplication No. 62/334,149, filed May 10, 2016, which are both hereinincorporated by reference.

FIELD

The present invention generally relates to compounds having activity asinhibitors of eukaryotic initiation factor 4A (eIF4A), such as eIF4AIand eIF4AII, as well as to related compositions and methods forutilizing the inventive compounds as therapeutic agents for treatment ofeIF4A dependent diseases, including the treatment of cancer.

BACKGROUND

Translation is the process where the sequence of an mRNA directs thesynthesis of a specific protein. The translation of most cellular mRNA,and especially those that contain highly structured 5′-UTRs or an IRESelement, depends on the formation of a functional eIF4F (eukaryoticinitiation factor 4F) complex consisting of eIF4A, eIF4E and eIF4G. A.Marintchev et al., Cell, 2009; 136, 447-460. These eIF4 proteins areinvolved in the initiation phase of translation and help catalyze therecruitment of mRNA to the 40S ribosomal subunit to form the 48Sinitiation complex. eIF4F recognizes the cap structure at the 5′-end ofmRNA through eIF4E, unwinds the secondary structure of the 5′-UTR regionthrough the helicase activity of eIF4A, and binds the 43S complexthrough interactions between eIF4G and eIF3. A. Parsyan et al., NatureReviews, Molecular Cell Biology, 2011; 12, 235-245.

The translation initiation factor eIF4A is a member of the “DEAD box”family of ATP-dependent helicases that acts as an RNA dependent ATPaseand ATP-dependent RNA helicase to facilitate mRNA binding to theribosome as part of the eIF4F complex. eIF4A consists of two distinctdomains connected through a short linker that are both required forfunction. The enzymatic activity of eIF4A is stimulated by formation ofa stable complex with eIF4G. The helicase activity of eIF4A either aloneor as part of the eIF4F complex is increased through a transientinteraction with eJF4B. eJF4A exists as a free form (eJF4A_(f)) and as asubunit of eJF4F (eIF4A_(c)) and is thought to cycle through the eIF4Fcomplex during initiation. When bound in the eIF4F complex, eIF4A_(c) is˜20-fold more efficient as an RNA helicase than when found alone,leading to the proposal that eIF4A_(c) is the functional helicase fortranslation initiation. The helicase activity of eIF4F (via eIF4A_(c))is thought to unwind local secondary structure in the 5′UTR of mRNAs tofacilitate cap-dependent ribosome recruitment. See, e.g., U. Harms etal., Nucleic Acids Research, 2014; 1-12; A. Andreou et al., RNA Biology,2013; 10, 19-32.

There are three eIF4A family members: eIF4AI, eIF4AII, and eIF4AIII.eIF4AI and eIF4AII show 90-95% similarity at the amino acid level, areinvolved in translation and are essential for growth and development. Inaddition to its role in translation initiation, isoform eIF4AII also hasbeen implicated in microRNA mediated mRNA silencing. eIF4AIII is 65%similar to the other two isoforms and is involved in nonsense-mediateddecay. All three eIF4A isoforms are members of the DEAD-box putative RNAhelicase protein family that are characterized by seven highly conservedamino acid sequence motifs implicated in RNA remodeling. These proteinsare involved in virtually all aspects of cellular RNA metabolism,including ribosome biogenesis, splicing, translation, and mRNAdegradation.

eIF4A selectively regulates the translation of a subset of mRNAs. Thisselectivity is a result of structural elements and sequence recognitionmotifs found within the 5′-UTR of the mRNA. Translation inhibition canalso be regulated by the tumor suppressor programmed cell death 4(PDCD4). PDCD4 is a negative regulator of translation that binds andsequesters eIF4A. The association of PDCD4 with eIF4A induces aconformational change that prevents eIF4G from binding with eIF4Ainhibiting translation initiation. C. Suzuki et al., PNAS, 2008; 105,3274-3279.

Regulation of translation is an increasingly important field as it hasimplications in a range of diseases. Translation initiation is ratelimiting and is dependent on the eukaryotic initiation factors.Alterations in the expression of eIF4A or factors (i.e. eIF4E, eIF4B andPDCD4) that alter its activity have been observed in many cancers. eIF4Eis a well-established oncogene that regulates the translation ofoncogenic mRNAs with long or structured 5′-UTRs. Overexpression ofeIF4A, eIF4E and eIF4B has been associated with poor prognosis indisease indications including lymphoma, lung, colon, liver, ovarian andbreast cancer. Decreased expression of PDCD4 has been linked to thedevelopment and progression of several types of cancer including lung,colon and liver. High levels of PDCD4 have been associated with goodoutcomes in certain types of breast cancer. See M. Bhat, Nature ReviewsDrug Discovery, 2014; 14 261-278; A Modelska et al., Cell Death andDisease, 2015; 6, e1603.

Accordingly, while advances have been made in this field there remains asignificant need in the art for compounds that specifically inhibiteFI4A activity, particularly with regard to eIF4A's role in regulationof cancer pathways, as well as for associated composition and methods.The present invention fulfills this need and provides further relatedadvantages.

SUMMARY

The present invention is directed to compounds that inhibit or modulatethe activity of eIF4A, as well as stereoisomers, tautomers andpharmaceutically acceptable salts of such compounds. The presentinvention also is directed to pharmaceutically acceptable compositionscontaining such compounds and associated methods for treating conditionsthat would benefit from eIF4A inhibition, such as cancer.

In one embodiment the invention is directed to compounds according toFormula I

or stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, wherein:

X is CR⁶R⁷, O, S, NH, N(C₁-C₈)alkyl, C(O), C═CR⁶R⁷, N(CO)R⁸, S(O) orS(O)₂;

Y is a 5-membered heteroaryl or a 6-membered aryl or heteroaryl;

R¹ and R² independently are aryl, heterocyclyl, heteroaryl orcycloalkyl;

R^(3a), R^(3b), R^(4a) and R^(4b) independently are H, halogen, CN,C₁-C₈(alkyl), (C₁-C₈)haloalkyl, C₂-C₈(alkenyl), (C₂-C₈)alkynyl, OR⁹,NHR⁹, NR⁹R⁹, [(C₁-C₈)alkylene]OR⁹, [(C₁-C₈)alkylene]NHR⁹,[(C₁-C₈)alkylene]NR⁹R⁹, C(O)R⁸, C(O)NHR⁹, C(O)NR⁹R⁹,C(O)[(C₁-C₈)alkylene]NHR⁹, C(O)[(C₁-C₈)alkylene]NR⁹R⁹, CO₂R⁹, C(S)NHR⁹,C(S)NR⁹R⁹, SR⁹, S(O)R⁹, SO₂R⁹, SO₂NHR⁹, SO₂NR⁹R⁹, NH(CO)R⁸, NR⁹(CO)R⁸,NH(CO)NHR⁹, NH(CO)NR⁹R⁹, NR⁹(CO)NHR⁹, NR⁹(CO)NR⁹R⁹, P(O)(OH)(OR⁹),P(O)(OR⁹) (OR⁹), aryl, heteroaryl, cycloalkyl or heterocyclyl;

R^(3a) and R^(3b), and R^(4a) and R^(4b) independently combine to formoxo or alkenyl, or a cycloalkyl or heterocyclyl ring; or

R^(3a) and R^(4a), R^(3b) and R^(4b) or R^(4a) and R⁵ together with thecarbon atom to which they are attached form a cycloalkyl or heterocyclylring; or

R² and R^(3a) together with the carbon atom to which they are attachedform a bicyclic ring system;

R⁵ is H, halogen, OH, CN, N₃, SR⁹, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl,O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl, (C₂-C₈)alkynyl, NHC(O)(C₁-C₈)alkyl orheteroaryl;

R⁶ and R⁷ independently are H, CN, halogen, OR⁹, SR⁹, (C₁-C₈)alkyl,NH(R⁹) or NR⁹R⁹;

R⁸ is H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, O(C₁-C₈)alkyl,O(C₁-C₈)haloalkyl, cycloalkyl, O(cycloalkyl), heterocyclyl,O(heterocyclyl), aryl, O(aryl), heteroaryl or O(heteroaryl);

R⁹ is H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, cycloalkyl, heterocyclyl,[(C₁-C₈)alkylene]heterocyclyl, aryl, [(C₁-C₈)alkylene]aryl orheteroaryl;

wherein the two R⁹'s together with the nitrogen atom to which they areattached of NR⁹R⁹, [(C₁-C₈)alkylene]NR⁹R⁹, C(O)NR⁹R⁹,C(O)[(C₁-C₈)alkylene]NR⁹R⁹, C(S)NR⁹R⁹, SO₂NR⁹R⁹, NH(CO)NR⁹R⁹ orNR⁹(CO)NR⁹R⁹, optionally form a heterocyclyl ring;

wherein any alkyl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl or arylis optionally substituted with 1, 2, or 3 groups selected from OH, CN,SH, SO₂NH₂, SO₂(C₁-C₄)alkyl, SO₂NH(C₁-C₄)alkyl, halogen, NH₂,NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂, C(O)NH₂, COOH, COOMe, acetyl,(C₁-C₈)alkyl, O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl,NH₂—C(O)-alkylene, NH(Me)-C(O)-alkylene, CH₂—C(O)-lower alkyl,C(O)-lower alkyl, alkylcarbonylaminyl, CH₂—[CH(OH)]_(m)—(CH₂)_(p)—OH,CH₂—[CH(OH)]_(m)—(CH₂)_(p)—NH₂ or CH₂-aryl-alkoxy;

or wherein any alkyl, cycloalkyl or heterocyclyl is optionallysubstituted with oxo;

“m” and “p” are 1, 2, 3, 4, 5 or 6; and

wherein when Y is a 6-membered aryl then X is not O.

In one embodiment the 6-membered aryl or heteroaryl is

wherein

A¹ is N or CR¹⁰;

A² is N or CR¹¹;

A³ is N or CR¹²;

A⁴ is N or CR¹³; and

R¹⁰, R¹¹, R¹² and R¹³ independently are H, halogen, C₁-C₈(alkyl),(C₁-C₈)haloalkyl, C(O)O(C₁-C₈)alkyl, C(O)(C₁-C₈)alkyl, SO₂(C₁-C₈)alkyl,C₂-C₈(alkenyl), (C₂-C₈)alkynyl, OR⁹, NHR⁹, NR⁹R⁹, CN,[(C₁-C₈)alkylene]OR⁹, [(C₁-C₈)alkylene]NHR⁹, [(C₁-C₈)alkylene]NR⁹R⁹,C(O)R⁸, C(O)NHR⁹, C(O)NR⁹R⁹, C(O)[(C₁-C₈)alkylene]NHR⁹,C(O)[(C₁-C₈)alkylene]NR⁹R⁹, CO₂R⁹, C(S)NHR⁹, C(S)NR⁹R⁹, SR⁹, S(O)R⁹,SO₂R⁹, SO₂NHR⁹, SO₂NR⁹R⁹, NH(CO)R⁸, NR⁹(CO)R⁸, NH(CO)NHR⁹, NH(CO)NR⁹R⁹,NR⁹(CO)NHR⁹, NR⁹(CO)NR⁹R⁹, P(O)(OH)(OR⁹), P(O)(OR⁹) (OR⁹), aryl,heteroaryl, cycloalkyl or heterocyclyl.

In one embodiment the 5-membered heteroaryl is

wherein any two of B¹, B² and B³ are CR¹⁴ and N and the remaining B ringatom is N(R¹⁵) or S, wherein R¹⁴ is H, CN, halogen, OR⁹, SR⁹,(C₁-C₈)alkyl, C(O)O(C₁-C₈)alkyl, C(O)(C₁-C₈)alkyl, SO₂(C₁-C₈)alkyl,SO₂NR⁹R⁹, C(O)NR⁹R⁹, NR⁹R⁹ or NR⁹C(O)R⁸, and R¹⁵ is H or (C₁-C₈)alkyl.

The present invention also provides a pharmaceutical compositioncomprising (i) a therapeutically effective amount of at least onecompound according to Formula I or a stereoisomer, a tautomer or apharmaceutically acceptable salt thereof; (ii) in combination with apharmaceutically acceptable carrier, diluent or excipient.

Also provided by the present invention is a method for attenuating orinhibiting the activity of eIF4A in at least one cell overexpressingeIF4A, comprising contacting the at least one cell with a compoundaccording to claim 1 or a stereoisomer, tautomer or pharmaceuticallyacceptable salt thereof.

According to the inventive method at least one cell is a colon cancercell, a gastric cancer cell, a thyroid cancer cell, a lung cancer cell,a leukemia cell, a B-cell lymphoma, a T-cell lymphoma, a hairy celllymphoma, Hodgkins lymphoma cell, non-Hodgkins lymphoma cell, Burkitt'slymphoma cell, a pancreatic cancer cell, a melanoma cell, a multiplemelanoma cell, a brain cancer cell, a CNS cancer cell, a renal cancercell, a prostate cancer cell, an ovarian cancer cell, or a breast cancercell.

According to yet another embodiment the invention provides a method fortreating a eIF4A dependent condition in a mammal in need thereofcomprising administering to the mammal (i) a therapeutically effectiveamount of at least one compound according to claim 1 or a stereoisomer,tautomer or pharmaceutically acceptable salt thereof, or (ii) apharmaceutical composition in accordance with the invention.

Compounds and pharmaceutically acceptable formulations in accordancewith the invention are useful for treating an eIF4A dependent conditionsuch as colon cancer, colorectal cancer, gastric cancer, thyroid cancer,lung cancer, leukemia, B-cell lymphoma, T-cell lymphoma, hairy celllymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, Burkitt's lymphoma,pancreatic cancer, melanoma, multiple melanoma, brain cancer, CNScancer, renal cancer, prostate cancer, ovarian cancer or breast cancer.

The above embodiments and other aspects of the invention are readilyapparent in the detailed description that follows. Various referencesare set forth herein which describe in more detail certain backgroundinformation, procedures, compounds and/or compositions, and are eachhereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

In the following description certain specific details are set forth inorder to provide a thorough understanding of various embodiments of theinvention. However, one skilled in the art will understand that theinvention may be practiced without these details. Unless the contextrequires otherwise, throughout the present specification and claims, theword “comprise” and variations thereof, such as, “comprises” and“comprising” are to be construed in an open, inclusive sense (i.e., as“including, but not limited to”).

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

DEFINITIONS

As used herein, and unless noted to the contrary, the following termsand phrases have the meaning noted below.

“Amino” refers to the —NH₂ substituent.

“Aminocarbonyl” refers to the —C(O)NH₂ substituent.

“Carboxyl” refers to the —CO₂H substituent.

“Carbonyl” refers to a —C(O)—, —(CO)— or —C(═O)— group. All notationsare used interchangeably within the specification.

“Cyano” refers to the —C≡N substituent.

“Cyanoalkylene” refers to the -(alkylene)C≡N substituent.

“Acetyl” refers to the —C(O)CH₃ substituent.

“Hydroxy” or “hydroxyl” refers to the —OH substituent.

“Hydroxyalkylene” refers to the -(alkylene)OH substituent.

“Oxo” refers to a ═O substituent.

“Thio” or “thiol” refer to a —SH substituent.

“Alkyl” refers to a saturated, straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms (C₁-C₁₂ alkyl), from one to eight carbon atoms(C₁-C₈ alkyl) or from one to six carbon atoms (C₁-C₆ alkyl), and whichis attached to the rest of the molecule by a single bond. Exemplaryalkyl groups include methyl, ethyl, n-propyl, 1-methylethyl(iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl),3-methylhexyl, 2-methylhexyl, and the like.

“Lower alkyl” has the same meaning as alkyl defined above but havingfrom one to four carbon atoms (C₁-C₄ alkyl).

“Alkenyl” refers to an unsaturated alkyl group having at least onedouble bond and from two to twelve carbon atoms (C₂-C₁₂ alkenyl), fromtwo to eight carbon atoms (C₂-C₈ alkenyl) or from two to six carbonatoms (C₂-C₆ alkenyl), and which is attached to the rest of the moleculeby a single bond, e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl,and the like.

“Alkynyl” refers to an unsaturated alkyl group having at least onetriple bond and from two to twelve carbon atoms (C₂-C₁₂ alkynyl), fromtwo to ten carbon atoms (C₂-C₁₀ alkynyl) from two to eight carbon atoms(C₂-C₈ alkynyl) or from two to six carbon atoms (C₂-C₆ alkynyl), andwhich is attached to the rest of the molecule by a single bond, e.g.,ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon (alkyl) chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, respectively. Alkylenescan have from one to twelve carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, and the like. The alkylene chain is attached tothe rest of the molecule through a single or double bond. The points ofattachment of the alkylene chain to the rest of the molecule can bethrough one carbon or any two carbons within the chain. “Optionallysubstituted alkylene” refers to alkylene or substituted alkylene.

“Alkenylene” refers to divalent alkene. Examples of alkenylene includewithout limitation, ethenylene (—CH═CH—) and all stereoisomeric andconformational isomeric forms thereof. “Substituted alkenylene” refersto divalent substituted alkene. “Optionally substituted alkenylene”refers to alkenylene or substituted alkenylene.

“Alkynylene” refers to divalent alkyne. Examples of alkynylene includewithout limitation, ethynylene, propynylene. “Substituted alkynylene”refers to divalent substituted alkyne.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl having the indicated number of carbon atoms as defined above.Examples of alkoxy groups include without limitation —O-methyl(methoxy), —O-ethyl (ethoxy), —O-propyl (propoxy), —O-isopropyl (isopropoxy) and the like.

“Alkylaminyl” refers to a radical of the formula —NHR_(a) or—NR_(a)R_(a) where each R_(a) is, independently, an alkyl radical havingthe indicated number of carbon atoms as defined above.

“Cycloalkylaminyl” refers to a radical of the formula —NHR_(a) or—NR_(a)R_(a) where R_(a) is a cycloalkyl radical as defined herein.

“Alkylcarbonylaminyl” refers to a radical of the formula —NHC(O)R_(a) or—NR_(a)C(O)R_(a), where R_(a) is an alkyl radical having the indicatednumber of carbon atoms as defined herein.

“Cycloalkylcarbonylaminyl” refers to a radical of the formula—NHC(O)R_(a) or —NR_(a)C(O)R_(a) where R_(a) is a cycloalkyl radical asdefined herein.

“Alkylaminocarbonyl” refers to a radical of the formula —C(O)NHR_(a) or—C(O)NR_(a)R_(a), where each R_(a) is independently, an alkyl radicalhaving the indicated number of carbon atoms as defined herein.

“Cyclolkylaminocarbonyl” refers to a radical of the formula—C(O)NHR_(a), where R_(a) is a cycloalkyl radical as defined herein.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. Exemplary aryls arehydrocarbon ring system radical comprising hydrogen and 6 to 9 carbonatoms and at least one aromatic ring; hydrocarbon ring system radicalcomprising hydrogen and 9 to 12 carbon atoms and at least one aromaticring; hydrocarbon ring system radical comprising hydrogen and 12 to 15carbon atoms and at least one aromatic ring; or hydrocarbon ring systemradical comprising hydrogen and 15 to 18 carbon atoms and at least onearomatic ring. For purposes of this invention, the aryl radical may be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. Aryl radicals include, but arenot limited to, aryl radicals derived from aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane,indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. “Optionally substituted aryl” refers to a aryl group or asubstituted aryl group.

“Arylene” denotes divalent aryl, and “substituted arylene” refers todivalent substituted aryl.

“Aralkyl” or “araalkylene” may be used interchangeably and refer to aradical of the formula —R_(b)—R_(e) where R_(b) is an alkylene chain asdefined herein and R_(c) is one or more aryl radicals as defined herein,for example, benzyl, diphenylmethyl and the like.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,three to nine carbon atoms, three to eight carbon atoms, three to sevencarbon atoms, three to six carbon atoms, three to five carbon atoms, aring with four carbon atoms, or a ring with three carbon atoms. Thecycloalkyl ring may be saturated or unsaturated and attached to the restof the molecule by a single bond. Monocyclic radicals include, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

“Cycloalkylalkylene” or “cycloalkylalkyl” may be used interchangeablyand refer to a radical of the formula —R_(b)R_(e) where R_(b) is analkylene chain as defined herein and R_(e) is a cycloalkyl radical asdefined herein. In certain embodiments, R_(b) is further substitutedwith a cycloalkyl group, such that the cycloalkylalkylene comprises twocycloalkyl moieties.

Cyclopropylalkylene and cyclobutylalkylene are exemplarycycloalkylalkylene groups, comprising at least one cyclopropyl or atleast one cyclobutyl group, respectively.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring may be replaced with anitrogen atom.

“Halo” or “halogen” refers to bromo (bromine), chloro (chlorine), fluoro(fluorine), or iodo (iodine).

“Haloalkyl” refers to an alkyl radical having the indicated number ofcarbon atoms, as defined herein, wherein one or more hydrogen atoms ofthe alkyl group are substituted with a halogen (halo radicals), asdefined above. The halogen atoms can be the same or different. Exemplaryhaloalkyls are trifluoromethyl, difluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like.

“Heterocyclyl”, heterocycle”, or “heterocyclic ring” refers to a stable3- to 18-membered saturated or unsaturated radical which consists of twoto twelve carbon atoms and from one to six heteroatoms, for example, oneto five heteroatoms, one to four heteroatoms, one to three heteroatoms,or one to two heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur. Exemplary heterocycles include withoutlimitation stable 3-15 membered saturated or unsaturated radicals,stable 3-12 membered saturated or unsaturated radicals, stable 3-9membered saturated or unsaturated radicals, stable 8-membered saturatedor unsaturated radicals, stable 7-membered saturated or unsaturatedradicals, stable 6-membered saturated or unsaturated radicals, or stable5-membered saturated or unsaturated radicals.

Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused, spiro or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of non-aromatic heterocyclyl radicals include, butare not limited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, thietanyl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Heterocyclylsinclude heteroaryls as defined herein, and examples of aromaticheterocyclyls are listed in the definition of heteroaryls below.

“Heterocyclylalkyl” or “heterocyclylalkylene” refers to a radical of theformula —R_(b)R_(f) where R_(b) is an alkylene chain as defined hereinand R_(f) is a heterocyclyl radical as defined above, and if theheterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl maybe attached to the alkyl radical at the nitrogen atom.

“Heteroaryl” or “heteroarylene” refers to a 5- to 14-membered ringsystem radical comprising hydrogen atoms, one to thirteen carbon atoms,one to six heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur, and at least one aromatic ring. For purposes of thisinvention, the heteroaryl radical may be a stable 5-12 membered ring, astable 5-10 membered ring, a stable 5-9 membered ring, a stable 5-8membered ring, a stable 5-7 membered ring, or a stable 6 membered ringthat comprises at least 1 heteroatom, at least 2 heteroatoms, at least 3heteroatoms, at least 4 heteroatoms, at least 5 heteroatoms or at least6 heteroatoms. Heteroaryls may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. The heteroatom may be a member of an aromatic ornon-aromatic ring, provided at least one ring in the heteroaryl isaromatic. Examples include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl).

“Heteroarylalkyl” or “heteroarylalkylene” refers to a radical of theformula —R_(b)R_(g) where R_(b) is an alkylene chain as defined aboveand R_(g) is a heteroaryl radical as defined above.

“Thioalkyl” refers to a radical of the formula —SR_(a) where R_(a) is analkyl radical as defined above containing one to twelve carbon atoms, atleast 1-10 carbon atoms, at least 1-8 carbon atoms, at least 1-6 carbonatoms, or at least 1-4 carbon atoms.

“Heterocyclylaminyl” refers to a radical of the formula —NHR_(f) whereR_(f) is a heterocyclyl radical as defined above.

“Thione” refers to a ═S group attached to a carbon atom of a saturatedor unsaturated (C₃-C₈)cyclic or a (C₁-C₈)acyclic moiety.

“Sulfoxide” refers to a —S(O)— group in which the sulfur atom iscovalently attached to two carbon atoms.

“Sulfone” refers to a —S(O)₂— or —(SO₂)— group in which a hexavalentsulfur is attached to each of the two oxygen atoms through double bondsand is further attached to two carbon atoms through single covalentbonds.

The term “oxime” refers to a —C(R_(a))═N—OR_(a) radical where R_(a) ishydrogen, lower alkyl, an alkylene or arylene group as defined above.

The compound of the invention can exist in various isomeric forms, aswell as in one or more tautomeric forms, including both single tautomersand mixtures of tautomers. The term “isomer” is intended to encompassall isomeric forms of a compound of this invention, including tautomericforms of the compound.

Some compounds described here can have asymmetric centers and thereforeexist in different enantiomeric and diastereomeric forms. A compound ofthe invention can be in the form of an optical isomer or a diastereomer.Accordingly, the invention encompasses compounds of the invention andtheir uses as described herein in the form of their optical isomers,diastereoisomers and mixtures thereof, including a racemic mixture.Optical isomers of the compounds of the invention can be obtained byknown techniques such as asymmetric synthesis, chiral chromatography, orvia chemical separation of stereoisomers through the employment ofoptically active resolving agents.

Unless otherwise indicated “stereoisomer” means one stereoisomer of acompound that is substantially free of other stereoisomers of thatcompound. Thus, a stereomerically pure compound having one chiral centerwill be substantially free of the opposite enantiomer of the compound. Astereomerically pure compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, for example greater than about 90%by weight of one stereoisomer of the compound and less than about 10% byweight of the other stereoisomers of the compound, or greater than about95% by weight of one stereoisomer of the compound and less than about 5%by weight of the other stereoisomers of the compound, or greater thanabout 97% by weight of one stereoisomer of the compound and less thanabout 3% by weight of the other stereoisomers of the compound.

If there is a discrepancy between a depicted structure and a name givento that structure, then the depicted structure controls. Additionally,if the stereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it. In some cases, however, where more than one chiralcenter exists, the structures and names may be represented as singleenantiomers to help describe the relative stereochemistry. Those skilledin the art of organic synthesis will know if the compounds are preparedas single enantiomers from the methods used to prepare them.

In this description a “pharmaceutically acceptable salt” is apharmaceutically acceptable, organic or inorganic acid or base salt of acompound of the invention. Representative pharmaceutically acceptablesalts include, e.g., alkali metal salts, alkali earth salts, ammoniumsalts, water-soluble and water-insoluble salts, such as the acetate,amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate,benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide,butyrate, calcium, calcium edetate, camsylate, carbonate, chloride,citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate,esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts. Apharmaceutically acceptable salt can have more than one charged atom inits structure. In this instance the pharmaceutically acceptable salt canhave multiple counterions. Thus, a pharmaceutically acceptable salt canhave one or more charged atoms and/or one or more counterions.

The terms “treat”, “treating” and “treatment” refer to the ameliorationor eradication of a disease or symptoms associated with a disease. Incertain embodiments, such terms refer to minimizing the spread orworsening of the disease resulting from the administration of one ormore prophylactic or therapeutic agents to a patient with such adisease. In the context of the present invention the terms “treat”,“treating” and “treatment” also refer to:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment;(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition; or(iv) relieving the symptoms resulting from the disease or condition,i.e., relieving pain without addressing the underlying disease orcondition. As used herein, the terms “disease” and “condition” may beused interchangeably or may be different in that the particular maladyor condition may not have a known causative agent (so that etiology hasnot yet been worked out) and it is therefore not yet recognized as adisease but only as an undesirable condition or syndrome, wherein a moreor less specific set of symptoms have been identified by clinicians. Theterm “effective amount” refers to an amount of a compound of theinvention or other active ingredient sufficient to provide a therapeuticor prophylactic benefit in the treatment or prevention of a disease orto delay or minimize symptoms associated with a disease. Further, atherapeutically effective amount with respect to a compound of theinvention means that amount of therapeutic agent alone, or incombination with other therapies, that provides a therapeutic benefit inthe treatment or prevention of a disease. Used in connection with acompound of the invention, the term can encompass an amount thatimproves overall therapy, reduces or avoids symptoms or causes ofdisease, or enhances the therapeutic efficacy or synergies with anothertherapeutic agent.

The terms “modulate”, “modulation” and the like refer to the ability ofa compound to increase or decrease the function, or activity of, forexample, eukaryotic initiation factor 4A (eIF4A), such as eIF4AI andeIF4AII. “Modulation”, in its various forms, is intended to encompassinhibition, antagonism, partial antagonism, activation, agonism and/orpartial agonism of the activity associated with eIF4A. eIF4A inhibitorsare compounds that bind to, partially or totally block stimulation,decrease, prevent, delay activation, inactivate, desensitize, or downregulate signal transduction. The ability of a compound to modulateeIF4A activity can be demonstrated in an enzymatic assay or a cell-basedassay.

A “patient” or subject” includes an animal, such as a human, cow, horse,sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbitor guinea pig. The animal can be a mammal such as a non-primate and aprimate (e.g., monkey and human). In one embodiment, a patient is ahuman, such as a human infant, child, adolescent or adult.

The term “prodrug” refers to a precursor of a drug, a compound whichupon administration to a patient, must undergo chemical conversion bymetabolic processes before becoming an active pharmacological agent.Exemplary prodrugs of compounds in accordance with Formula I are esters,acetamides, and amides.

Compounds of the Invention

The present invention is directed to compounds according to Formula I,

or stereoisomers, tautomers or pharmaceutically acceptable saltsthereof.

In one embodiment X is CR⁶R⁷ or O. In another embodiment X is CH₂ or O.

In one embodiment Y is a 6-membered heteroaryl wherein A¹ is N, A² isCR¹¹, A³ is CR¹² and A⁴ is CR¹³, wherein R¹¹, R¹² and R¹³ independentlyare H, CN, halogen or OR⁹.

In another embodiment Y is a 6-membered heteroaryl wherein A² is N, A¹is CR¹⁰, A³ is CR¹² and A⁴ is CR¹³, wherein R¹⁰, R¹² and R¹³independently are H, CN, halogen or OR⁹. In another embodiment Y is a6-membered heteroaryl wherein A³ is N, A¹ is CR¹⁰, A² is CR¹¹ and A⁴ isCR¹³, wherein R¹⁰, R¹¹ and R¹³ independently are H, CN, halogen or OR⁹.

In another embodiment Y is a 6-membered heteroaryl wherein A⁴ is N, A¹is CR¹⁰, A² is CR¹¹ and A³ is CR¹², wherein R¹⁰, R¹¹ and R¹²independently are H, CN, halogen or OR⁹.

In another embodiment Y is a 6-membered heteroaryl wherein A² and A⁴ areN, A¹ is CR¹⁰ and A³ is CR¹², wherein R¹⁰ and R¹² independently are H,CN, halogen or OR⁹. In one embodiment Y is a 5-membered heteroarylwherein B¹ and B³ are N or S and B² is CR¹⁴ wherein R¹⁴ is H, CN,halogen or OR⁹.

In another embodiment Y is a 5-membered heteroaryl wherein B¹ is N, B²is NR¹⁵ and B³ is CR¹⁴, wherein R¹⁴ is H and R¹⁵ is OR⁹ or C₁-C₆(alkyl).

In another embodiment R¹ and R² are aryl.

In another embodiment R^(3a), R^(3b), R^(4a) and R^(4b) independentlyare H, halogen, C₁-C₈(alkyl), (C₁-C₈)haloalkyl, OH, CN,[(C₁-C₈)alkylene]OR⁹, [(C₁-C₈)alkylene]NHR⁹, [(C₁-C₈)alkylene]NR⁹R⁹,C(O)NH₂, C(O)NHR⁹, C(O)NR⁹R⁹, C(O)R⁹, CO₂R⁹, C(S)NH₂, S(O)R⁹, SO₂R⁹,SO₂NHR⁹, SO₂NR⁹R⁹, heteroaryl or cycloalkyl, wherein R⁹ is aC₁-C₈(alkyl) or (C₁-C₈)haloalkyl, or wherein the two R⁹'s together withthe nitrogen atom to which they are attached of [(C₁-C₈)alkylene]NR⁹R⁹,C(O)NR⁹R⁹ or SO₂NR⁹R⁹, optionally form a heterocyclyl ring.

In another embodiment R^(3b) is [(C₁-C₈)alkylene]NHR⁹ or[(C₁-C₈)alkylene]NR⁹R⁹, wherein R⁹ is C₁-C₈(alkyl) or (C₁-C₈)haloalkyl,or wherein the two R⁹'s together with the nitrogen atom to which theyare attached of [(C₁-C₈)alkylene]NR⁹R⁹ optionally form a heterocyclylring.

In another embodiment R^(4b) is OH.

In another embodiment R^(4a) and R^(4b) combine to form oxo or alkenyl.

In another embodiment R^(3a) and R^(4a), R^(3b) and R^(4b) or R^(4a) andR⁵ together with the carbon atom to which they are attached form acycloalkyl or heterocyclyl ring;

In another embodiment R⁵ is OH.

In another embodiment R⁶ and R⁷ are H or C₁-C₈(alkyl).

In another embodiment R⁹ is H or C₁-C₈(alkyl). In another embodiment R⁹is CH₃.

In another embodiment, the compounds according to Formula I are selectedfrom

-   Rac-(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-3-methoxy-5a-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 1F),-   (5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 2F),-   (5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 3F),-   (5aR,6S,7R,8R,8aS)-3-cyano-8,8a-dihydroxy-5a-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 4F),-   (5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 5F),-   (5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-3-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 6F),-   (5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(p-tolyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 7F),-   (5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 8F),-   (5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 9F),-   (5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-fluorophenyl)-88a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 10F),-   (5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 11F),-   (5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-5a-(4-(methylsulfonyl)phenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No.-   12F),-   Rac-(1R,2R,3 S,3    aR,8bS)-6-cyano-3a-(4-cyanophenyl)-1,8b-dihydroxy-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxamide    (Cpd. No. 13F),-   Rac-(5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide    (Cpd. No. 14F),-   Rac-(4bS,5R,6R,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-2-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxamide    (Cpd. No. 15F),-   (5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 16F),-   (5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(4-(trifluoromethoxy)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 17F),-   (5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 18F),-   Rac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide    (Cpd. No. 19F),-   (5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 20F),-   Rac-methyl    (4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-2-methyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate    (Cpd. No. 21F),-   Rac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide    (Cpd. No. 22F),-   (4aR,5    S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide    (Cpd. No. 23F),-   Rac-methyl    (5aR,6R,6aS,7aS,7bR)-3-chloro-5a-(4-cyanophenyl)-7b-hydroxy-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxylate    (Cpd. No. 24F),-   Rac-methyl    (5aR,6R,6aS,7aS,7bR)-3-chloro-5a-(4-cyanophenyl)-7b-hydroxy-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxylate    (Cpd. No. 25F),-   Rac-4-((5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-7-(oxazol-2-yl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 26F),-   Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbothioamide    (Cpd. No. 27F),-   Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbothioamide    (Cpd. No. 28F),-   Rac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-3,8,8a-trihydroxy-N,N-dimethyl-6-phenyl-2-(trifluoromethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 29F),-   Rac-4-((5aR,6S,7S,8R,8aS)-7-(aminomethyl)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 30F),-   Rac-(5aR,6R,6aS,7aS,7bR)-3-chloro-5a-(4-cyanophenyl)-7b-hydroxy-N,N-dimethyl-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxamide    (Cpd. No. 31F),-   Rac-(5aR,6S,7R,8aR)-3-chloro-5a-(4-cyanophenyl)-8a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 32F),-   Rac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N,8-trimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 33Fa) and    Rac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N,8-trimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 33Fb),-   Rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8-methylene-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol    (Cpd. No. 34F),-   Rac-(5aR,6R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-methoxy-N,N-dimethyl-6-phenyl-5a,8a-dihydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 35F),-   Rac-(4aR,5S,6R,7R,7aS)-3-chloro-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide    (Cpd. No. 36F),-   Rac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-3-chloro-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide    (Cpd. No. 37F),-   Rac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-6,7-dihydrospiro[cyclopenta[4,5]furo[3,2-b]pyridine-8,2′-oxetan]-8a(5aH)-ol    (Cpd. No. 38F),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-7-((methylamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 39F),-   Rac-4-((5aR,6S,7R,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 40Fa),-   rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 40Fb),-   and    rac-4-((5aR,6S,7S,8S,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 40Fc)-   Rac-4-((5 aR,6S,7R,8R,8    aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 41Fa),-   rac-4-((5    aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 41Fb),-   and    rac-4-((5aR,6S,7S,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 41Fc),-   Rac-(1R,2R,3S,3aR,8bS)-8b-azido-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3-dihydro-1H-cyclopenta[b]benzofuran-2-carboxamide    (Cpd. No. 42F),-   Rac-methyl    (5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-fluoro-8-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate    (Cpd. No. 43F),-   Rac-(1R,2R,3S,3aR,8bS)-8b-amino-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-carboxamide    (Cpd. No. 44F),-   Rac-(1R,2R,3S,3    aR,8bS)-8b-acetamido-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-carboxamide    (Cpd. No. 45F),-   Rac-dimethyl    2-[[(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-6,7-dihydrocyclopenta[4,5]furo[1,2-b]pyridin-7-yl]methyl]propanedioate    (Cpd. No. 46F),-   Rac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile    (Cpd. No. 47F),-   Rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8-ethynyl-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol    (Cpd. No. 48F),-   Rac-methyl    (5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-cyano-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate    (Cpd. No. 49F),-   Rac-methyl    (5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate    (Cpd. No. 50F),-   Rac-(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 51F),-   Rac-(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 52F),-   Rac-(3aR,3bS,8aR,9R,9aR)-8a-(4-bromophenyl)-6-chloro-3b-hydroxy-9-phenyl-1,3a,3b,8a,9,9a-hexahydro-2H-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-2-one    (Cpd. No. 53F),-   Rac-4-((3    aR,3bS,8aR,9R,9aR)-6-chloro-3b-hydroxy-2-oxo-9-phenyl-1,2,3a,3b,9,9a-hexahydro-8aH-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-8a-yl)benzonitrile    (Cpd. No. 54F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol    (Cpd. No. 55F),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-7-(hydroxymethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 56F),-   Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-methyl-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol    (Cpd. No. 57F),-   Rac-methyl    (5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7-fluoro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate    (Cpd. No. 58F),-   Rac-methyl    (5aR,6S,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-7-fluoro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate    (Cpd. No. 59F),-   Rac-(2aS,3S,3    aR,8bS,8cR)-3a-(4-bromophenyl)-6-chloro-3-phenyl-2a,3,3a,8c-tetrahydrooxeto[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-8b(2H)-ol    (Cpd. No. 60F),-   Rac-(2aS,3S,3    aR,8bS,8cR)-3a-(4-bromophenyl)-6-chloro-3-phenyl-2a,3,3a,8c-tetrahydrooxeto[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-8b(2H)-ol    (Cpd. No. 61F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(methoxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol    (Cpd. No. 62F),-   Rac-(1 aS,3S,3    aR,8bS)-3a-(4-bromophenyl)-6-chloro-3-phenyl-1a,2,3,3a-tetrahydro-oxireno[2″,3″:    1′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine (Cpd. No. 63F),-   (4bS,5R,6R,7S,7aR)-7a-(4-Cyanophenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 64F),-   Rac-4-((4bS,5R,6S,7S,7aR)-6-(aminomethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 65F),-   4-((4bS,5R,6S,7S,7aR)-6-((Dimethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 66F),-   4-((4bS,5R,6S,7S,7aR)-4b,5-Dihydroxy-4-methoxy-7-phenyl-6-(piperazin-1-ylmethyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 67F),-   Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((4-methylpiperazin-1-yl)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 68F),-   Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methylamino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 69F),-   Rac-4-((4bS,5R,6S,7S,7aR)-6-((ethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)cyclohexa-1,3-diene-1-carbonitrile    (Cpd. No. 70F),-   Rac-4-((4bS,5R,6S,7S,7aR)-6-(azetidin-1-ylmethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 71F),-   Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(pyrrolidin-1-ylmethyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 72F),-   4-((4bS,5R,6S,7S,7aR)-6-((Diethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 73F),-   Rac-4-((4bS,5R,6S,7S,7aR)-6-((ethyl(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 74F),-   Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxyethyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 75F),-   Rac-4-((4bS,5R,6S,7S,7aR)-6-((benzyl(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 76F),-   Rac-4-((4bS,5R,6S,7S,7aR)-6-((benzylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 77F),-   Rac-4-((5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(((pyridin-3-ylmethyl)amino)methyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 78F),-   Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxyethyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 79F),-   Rac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-2-isopropyl-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide    (Cpd. No. 80F),-   4-((3aR,4R,4aR,9bS,9cR)-9b-Hydroxy-9-methoxy-2-oxo-4-phenyl-2,3,3a,4,9b,9c-hexahydro-4aH-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-4a-yl)benzonitrile    (Cpd. No. 81F),-   Rac-(4aR,5S,6R,7R,7aS)-3-cyano-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide    (Cpd. No. 82F),-   4-((5aR,6S,7R,8S,8aS)-3-Chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylsulfonyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 83F),-   Rac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7-(methylsulfonyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol    (Cpd. No. 84F),-   Rac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-7-(methylsulfonyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 85F),-   (5aR,6S,7R,8S,8aS)-5a-(4-Cyanophenyl)-8,8a-dihydroxy-7-(methylsulfonyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-3-carbonitrile    (Cpd. No. 86F),-   Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(morpholino)methanone    (Cpd. No. 87F),-   Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-N-(2,2,2-trifluoroethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 88F),-   Rac-(4bS,5R,6R,7S,7    aR)-7a-(4-bromophenyl)-N-cyclopropyl-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 89F),-   Rac-(4bS,5R,6R,7S,7    aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-N-(2,2,2-trifluoroethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 90F),-   Rac-(5    aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7,7-difluoro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol    (Cpd. No. 91F),-   Rac-(5aR,6R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6-dihydrospiro[cyclopenta[4,5]furo[3,2-b]pyridine-7,    1′-cyclopropane]-8,8a(8H)-diol (Cpd. No. 92F),-   Rac-(5    aR,6S,7R,8S,8aS)-7-(benzylsulfonyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8    aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd. No. 93F),-   Rac-4-((5aR,6S,7R,8S,8aS)-7-(benzylsulfonyl)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5    aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No.    94F),-   (4bS,5R,6R,7S,7    aR)-7a-(4-Cyanophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 95F),-   Rac-(4bS,5R,6R,7S,7    aR)-4-cyano-7a-(4-cyanophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 96F),-   Rac-(4bS,5R,6R,7S,7    aR)-7a-(4-bromophenyl)-4-chloro-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 97F),-   (4bS,5R,6R,7S,7 aR)-4-Chloro-7a-(4-cyanophenyl)-4b,5-dihydroxy-N,    N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 98F),-   Rac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide    (Cpd. No. 99F),-   Rac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide    (Cpd. No. 100F),-   Rac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(methylsulfonyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol    (Cpd. No. 101F),-   4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(methylsulfonyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 102F),-   4-((4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 103F),-   (5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 104F),-   (5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-3-carbonitrile    (Cpd. No. 105F),-   (4bS,5R,6S,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol    (Cpd. No. 106F),-   (4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol    (Cpd. No. 107F),-   (5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol    (Cpd. No. 108F),-   (5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol    (Cpd. No. 109F),-   4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(morpholinomethyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 110F),-   Rac-(4bS,5R,6R,7S,7    aR)-7a-(4-bromophenyl)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 111F),-   4-((4bS,5R,6S,7S,7aR)-6-(((2,2-difluoroethyl)(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 112F),-   4-((4bS,5R,6S,7S,7aR)-6-((4,4-difluoropiperidin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 113F),-   Rac-((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone    (Cpd. No. 114F),-   4-((4bS,5R,6S,7S,7aR)-6-(((2,2-difluoroethyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 115F),-   Rac-(4bS,5R,6R,7S,7    aR)-7a-(4-bromophenyl)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 116F),-   Rac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-((2,2,2-trifluoroethyl)sulfonyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol    (Cpd. No. 117F),-   Rac-4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(phenylsulfonyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 118F),-   Rac-4-((4bS,5    S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(pyridin-2-ylsulfonyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 119F),-   4-((4bR,5R,7S,7aR)-4b-hydroxy-5-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 120F),-   Rac-((4bS,5R,6R,7    S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(3,3-difluoroazetidin-1-yl)methanone    (Cpd. No. 121F),-   4-((4bS,5R,6S,7S,7aR)-6-((3,3-difluoroazetidin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)    benzonitrile (Cpd. No. 122F),-   Rac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide    (Cpd. No. 123F),-   Rac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide    (Cpd. No. 124F),-   Rac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide    (Cpd No. 125F),-   4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(morpholinosulfonyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 126F),-   Rac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol    (Cpd. No. 127F),-   Rac-4-((5aR,6S,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 128F),-   Rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one    (Cpd. No. 129F),-   Rac-(5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol    (Cpd. No. 130F),-   Rac-4-((5aR,6S,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 131F),-   Rac-N-((5aR,6S,8aS)-5a-(4-bromophenyl)-3-choro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylidene)-4-methylbenzenesulfonohydrazide    (Cpd. No. 132F),-   Rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6-dihydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol    (Cpd. No. 133F),-   Rac-methyl    (4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate    (Cpd. No. 134F),-   Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4,4-difluoropiperidin-1-yl)methanone    (Cpd. No. 135F),-   Rac-methyl    (5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate    (Cpd. No. 136F),-   Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide    (Cpd. No. 137F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol    (Cpd. No. 138F),-   (5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 139F),-   4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 140F),-   Rac-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 141F),-   Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol    (Cpd. No. 142F),-   Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol    (Cpd. No. 143F),-   Rac-(5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol    (Cpd. No. 144F),-   (5aR,6S,7S,8R,8aS)-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 145F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 146F),-   (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 147F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol    (Cpd. No. 148F),-   Rac-(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol    (Cpd. No. 149F),-   Rac-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-3-(methylamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 150F),-   (5aR,6S,7S,8R,8aS)-5a-(4-Cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 151F),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 152F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoropyrrolidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 153F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 154F),-   Rac-(5aR,6S,7S,8R,8aS)-7-((tert-butylamino)methyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 155F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((4-fluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 156aF),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((4-fluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 156bF),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((4-fluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 156cF),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 157aF),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 157bF),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 157cF),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-5a,78,    8a-tetrahydro-6H-cyopepenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 158aF),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 158bF),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-5a,78,    8a-tetrahydro-6H-cyopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 158cF),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 159aF),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 159bF),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 159cF),-   Rac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol    (Cpd. No. 160aF),-   Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol    (Cpd. No. 160bF),-   Rac-methyl    (1aS,2R,3S,3aR,8bS)-3a-(4-bromophenyl)-6-chloro-3-phenyl-1a,2,3,3a-tetrahydro-oxireno[2″,3″:    1′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-2-carboxylate (Cpd.    No. 161F),-   Rac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol    (Cpd. No. 162F),-   Rac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylsulfonyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol    (Cpd. No. 163F),-   Rac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyridin-2-ylsulfonyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 164F),-   Rac-(5    aR,6S,8S,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol    (Cpd. No. 165),-   Rac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol    (Cpd. No. 166F),-   Rac-4-((5aR,6S,8R,8    aR)-3-chloro-8a-hydroxy-8-(hydroxymethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 167F),-   Rac-4-((5aR,6S,8S,8aR)-3-chloro-8a-hydroxy-8-(hydroxymethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 168F),-   Rac-(2aR,3S,3aR,8bS,8cR)-3a-(4-bromophenyl)-6-chloro-8b-hydroxy-3-phenyl-3,3a,8b,8c-tetrahydrooxeto[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-2(2aH)-one    (Cpd. No. 169F),-   Rac-(4bR,5R,6R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol    (Cpd. No. 170F),-   Rac-4-((4bR,5R,6R,7S,7aR)-5-(aminomethyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 171F),-   Rac-(4bR,5R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol    (Cpd. No. 172F),-   Rac-4-((4bR,5R,7S,7aR)-5-(aminomethyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 173F),-   Rac-(5aR,6S,8R,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol    (Cpd. No. 174F),-   Rac-4-((5aR,6S,8R,8aR)-8-(aminomethyl)-3-chloro-8a-hydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 175F),-   Rac-(5aR,6S,8R,8aR)-8-(aminomethyl)-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-3-carbonitrile    (Cpd. No. 176F),-   Rac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol    (Cpd. No. 177F),-   Rac-4-((5aR,6S,8R,8aR)-3-chloro-8a-hydroxy-8-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 178F),-   Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-(morpholinomethyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol    (Cpd. No. 179F),-   Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-(morpholino-methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 180F),-   Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-(((2,2-difluoroethyl)amino)methyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol    (Cpd. No. 181F),-   Rac-4-((4bR,5R,6R,7S,7aR)-5-(((2,2-difluoroethyl)amino)methyl)-4b-hydroxy-6-(hydroxyl-methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 182F),-   Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((4-methylpiperazin-1-yl)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol    (Cpd. No. 183F),-   Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-((4-methyl-piperazin-1-yl)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 184F),-   Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((oxetan-3-ylamino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol    (Cpd. No. 185F),-   Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-((oxetan-3-ylamino)-methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)-benzonitrile    (Cpd. No. 186F),-   Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5-(((pyridin-4-ylmethyl)amino)methyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol    (Cpd. No. 187F),-   Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-5-(((pyridin-4-ylmethyl)amino)methyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 188F),-   Rac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyridin-2-ylthio)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile    (Cpd. No. 189F),-   Rac-(5aR,6S,8aS)-5a-(4-bromophenyl)-3-chloro-8-ethynyl-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 190F),-   Rac-(5aR,6S,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-8-(prop-1-yn-1-yl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide    (Cpd. No. 191F),-   Rac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-N,N-dimethyl-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 192F),-   Rac-methyl    (4bS,5R,6R,7aR)-4b,5-dihydroxy-7a-(4-iodophenyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate    (Cpd. No. 193F),-   Rac-4-((4bS,5R,6S,7S,7aR)-6-((4-acetylpiperazin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 194F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol    (Cpd. No. 195F),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 196F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 197F),-   4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 198aF),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 198bF),-   Rac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-1-methoxy-8-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol    (Cpd. No. 199F),-   Rac-(5aR,6S,7R,8R,8aR)-5a-(4-cyanophenyl)-8a-hydroxy-7-(hydroxymethyl)-1-methoxy-8-(morpholinomethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 200F),-   Rac-(4bR,5R,6R,7S,7aR)-5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol    (Cpd. No. 201F),-   Rac-4-((4bR,5R,6R,7S,7aR)-5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 202F),-   Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol    (Cpd. No. 203F),-   Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 204F),-   Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-((dimethylamino)methyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol    (Cpd. No. 205F),-   Rac-4-((4bR,5R,6R,7S,7aR)-5-((dimethylamino)methyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 206F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 207aF),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 207bF),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-(((2,2-difluoroethyl)(methyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 208aF),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-(((2,2-difluoroethyl)(methyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 208bF),-   Rac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-((dimethylamino)methyl)-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol    (Cpd. No. 209F),-   Rac-(5aR,6S,7R,8R,8aR)-5a-(4-cyanophenyl)-8-((dimethylamino)methyl)-8a-hydroxy-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 210F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3-fluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 211aF),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3-fluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 211bF),-   (5aR,6S,7S,8R,8aS)-7-(Azetidin-1-ylmethyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 212F),-   Rac-(5aR,6S,7R,8R,8aR)-5a-(4-cyanophenyl)-8-((4,4-difluoropiperidin-1-yl)methyl)-8a-hydroxy-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 213F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-dimethylmorpholino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol    (Cpd. No. 214F),-   Rac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3-(difluoromethyl)azetidin-1-yl)methanone    (Cpd. No. 215F),-   Rac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3-(difluoromethyl)azetidin-1-yl)methanone    (Cpd. No. 216F),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 217F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 218F),-   Rac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methanone    (Cpd. No. 219F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol    (Cpd. No. 220F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 221F),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 222F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-7-((methylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol    (Cpd. No. 223F),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-((methylamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 224F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-((methylamino)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 225F),-   Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-((tert-butylamino)methyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol    (Cpd. No. 226F),-   Rac-(5aR,6S,7R,8S,8aR)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile    (Cpd. No. 227F),-   Rac-(5aR,6S,7R,8S,8aR)-3-chloro-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile    (Cpd. No. 228F),-   Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide    (Cpd. No. 229F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol    (Cpd. No. 230F),-   4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 231F),-   Rac-4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 232F),-   4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl(2,2,2-trifluoroethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 233F),-   Rac-(4bR,5R,7S,7aR)-7a-(4-(aminomethyl)phenyl)-5-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol    (Cpd. No. 234F),-   Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone    (Cpd. No. 235F),-   Rac-4-((4bS,5R,6S,7S,7aR)-6-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 236F),-   Rac-(4bS,5R,6R,7S,7    aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-N-(oxetan-3-yl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 237F),-   Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl(oxetan-3-yl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 238F),-   Rac-(4bS,5R,6R,7S,7    aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(oxetan-3-yl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 239F),-   Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((oxetan-3-ylamino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 240F),-   Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 241F),-   Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 242F),-   4-((4bS,5R,6S,7S,7aR)-6-((tert-butyl(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 243F),-   Rac-4-((4bS,5R,6S,7S,7aR)-6-((cyclopropylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 244F),-   Rac-(4bS,5R,6R,7S,7    aR)-7a-(4-bromophenyl)-N-cyclopropyl-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 245F),-   Rac-4-((4bS,5R,6S,7S,7aR)-6-((cyclopropyl(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 246F),-   Rac-(4bS,5R,6R,7S,7    aR)-7a-(4-bromophenyl)-N-(2-fluoroethyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 247F),-   4-((4bS,5R,6S,7S,7aR)-6-(((2-fluoroethyl)(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 248F),-   Rac-(4bS,5R,6R,7S,7    aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 249F),-   4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 250F),-   Rac-(4bS,5R,6R,7S,7    aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxy-2-methylpropyl)-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 251F),-   4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxy-2-methylpropyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 252F),-   Rac-(4bS,5R,6R,7S,7    aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxy-2-methylpropyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 253F),-   4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxy-2-methylpropyl)amino)methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 254F),-   Rac-(4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(p-tolyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol    (Cpd. No. 255F),-   (4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(p-tolyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol    (Cpd. No. 256F),-   Rac-((4bS,5R,6R,7 S,7    aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(piperidin-1-yl)methanone    (Cpd. No. 257F),-   4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(piperidin-1-ylmethyl)-4b,5,6,7-tetrahydro-7    aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.    258F),-   Rac-4-((4bS,5R,6S,7S,7aR)-6-(((2-fluoroethyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 259F),-   Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(2-methoxyethyl)-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 260F),-   4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(((2-methoxyethyl)(methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 261F),-   Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(2-methoxyethyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 262F),-   4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(((2-methoxyethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    hydrochloride (Cpd. No. 263F),-   Rac-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone    (Cpd. No. 264F),-   4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)    methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 265F),-   Rac-((1R,5S)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone    (Cpd. No. 266F),-   Rac-4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 267F),-   4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 268F),-   Rac-(3    aR,4R,4aR,9bS,9cR)-4a-(4-(difluoromethyl)phenyl)-9b-hydroxy-9-methoxy-4-phenyl-3,3a,4,4a,9b,9c-hexahydro-2H-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-2-one    (Cpd. No. 269F),-   Rac-(4bS,5R,6R,7R,7aR)-6-amino-7a-(4-(difluoromethyl)phenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol    (Cpd. No. 270F),-   Rac-((4bS,5R,6R,7S,7aR)-7a-(4-chlorophenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 271F),-   (4bS,5R,6S,7S,7aR)-7a-(4-Chlorophenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol    (Cpd. No. 272F),-   Rac-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone    (Cpd. No. 273F),-   4-((4bS,5R,6S,7S,7aR)-6-((6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 274F),-   Rac-(3    aR,4S,4aR,9bS,9cR)-4a-(4-bromophenyl)-9b-hydroxy-9-methoxy-4-phenyl-3,3a,4,4a,9b,9c-hexahydro-2H-furo[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-2-one    (Cpd. No. 275F),-   Rac-4-((4bS,5R,6R,7S,7aR)-6-(2-(dimethylamino)ethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 276F),-   Rac-(4bS,5R,6R,7S,7    aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-N-(pyridin-3-ylmethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 277F),-   4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl(pyridin-3-ylmethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 278F),-   Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(3,3-difluoropyrrolidin-1-yl)methanone    (Cpd. No. 279F),-   4-((4bS,5R,6S,7S,7aR)-6-((3,3-difluoropyrrolidin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 280F),-   Rac-((4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(morpholino)methanone    (Cpd. No. 281F),-   (4bS,5R,6S,7S,7aR)-4-Methoxy-6-(morpholinomethyl)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol    (Cpd. No. 282F),-   Rac-(4bS,5R,6S,7S,7aR)-4-methoxy-6-((4-methylpiperazin-1-yl)methyl)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol    (Cpd. No. 283F),-   (4bS,5R,6S,7S,7aR)-4-Methoxy-6-((4-methylpiperazin-1-yl)methyl)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol    (Cpd. No. 284F),-   Rac-(4bS,5R,6R,7S,7aR)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide    (Cpd. No. 285F),-   (4bS,5R,6S,7S,7aR)-6-(((2,2-Difluoroethyl)amino)methyl)-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol    (Cpd. No. 286F),-   Rac-4-((4bS,5R,7S,7aR)-4b,5-dihydroxy-4-methoxy-5-(morpholinomethyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 287F),-   (5aR,6S,7S,8R,8aS)-5a-(4-Cyanophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 288F),-   Rac-(4bR,7S,7aR)-4-methoxy-5-(morpholinomethyl)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol    (Cpd. No. 289F),-   4-((4bS,5R,6S,7S,7aR)-6-((tert-butylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 290F),-   4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(((2,2,2-trifluoroethyl)amino)methyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 291F),-   Rac-(5aR,6S,7S,8R,8aS)-7-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol    (Cpd. No. 292F),-   Rac-(5aR,6S,7S,8R,8aS)-7-(aminomethyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 293F),-   Rac-4-((5aR,6S,7S,8R,8aS)-7-(aminomethyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 294F), and-   Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylic    acid (Cpd. No. 295F).

In another embodiment, the compounds according to Formula I are selectedfrom

-   (5aR,6S,7S,8R,8aS)-7-((Dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 147F),-   4-((5aR,6S,7S,8R,8aS)-3-Chloro-8,8a-dihydroxy-1-methoxy-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 198aF),-   (5aR,6S,7S,8R,8aS)-7-(Azetidin-1-ylmethyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 212F),-   (5aR,6S,7S,8R,8aS)-5a-(4-Chlorophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 145F),-   Rac-(5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol    (Cpd. No. 144F),-   Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol    (Cpd. No. 143F),-   Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol    (Cpd. No. 142F),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 196F),-   (5aR,6S,7S,8R,8aS)-5a-(4-Cyanophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 139F),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 207bF),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 152F),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 157bF),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 158bF),-   4-((5aR,6S,7S,8R,8aS)-7-((Dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 231F),-   Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 159bF),-   4-((5aR,6S,7S,8R,8aS)-3-Chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile    (Cpd. No. 140F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 146F),-   (5aR,6S,7S,8R,8aS)-5a-(4-Cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 151F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 197F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 207aF),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 157cF),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoropyrrolidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 153F),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 159cF),-   Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-5a,78,    8a-tetrahydro-6H-cyopepenta[4,5]furo[3,2-c]pyridine-3-carbonitrile    (Cpd. No. 158cF),-   Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-(morpholino-methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 180F),-   Rac-4-((4bR,5R,6R,7S,7aR)-5-((dimethylamino)methyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 206F),-   4-((4bS,5R,6S,7S,7aR)-6-((Dimethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile    (Cpd. No. 66F),-   (4bS,5R,6S,7S,7aR)-7a-(4-Chlorophenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol    (Cpd. No. 272F),-   (4bS,5R,6S,7S,7aR)-7a-(4-(Difluoromethyl)phenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol    (Cpd. No. 106F), and-   (4bS,5R,6S,7S,7aR)-6-((Dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol    (Cpd. No. 107F).

In another embodiment the compounds according to Formula I are selectedfrom those presented in Table 1.

The inventive compounds according to Formula I may beisotopically-labeled by having one or more atoms replaced by an atomhaving a different atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of according to Formula I includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine,chlorine, or iodine. Illustrative of such isotopes are ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I,respectively. These radiolabeled compounds can be used to measure thebiodistribution, tissue concentration and the kinetics of transport andexcretion from biological tissues including a subject to which such alabeled compound is administered. Labeled compounds are also used todetermine therapeutic effectiveness, the site or mode of action, and thebinding affinity of a candidate therapeutic to a pharmacologicallyimportant target. Certain radioactive-labeled compounds according toFormula I, therefore, are useful in drug and/or tissue distributionstudies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e.¹⁴C, are particularly useful for this purpose in view of their ease ofincorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, affordscertain therapeutic advantages resulting from the greater metabolicstability, for example, increased in vivo half-life of compoundscontaining deuterium. Substitution of hydrogen with deuterium may reducedose required for therapeutic effect, and hence may be preferred in adiscovery or clinical setting. Substitution with positron emittingisotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, provides labeled analogs of theinventive compounds that are useful in Positron Emission Tomography(PET) studies, e.g., for examining substrate receptor occupancy.Isotopically-labeled compounds according to Formula I, can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the Preparations andExamples section as set out below using an appropriate isotopic-labelingreagent.

Embodiments of the invention disclosed herein are also meant toencompass the in vivo metabolic products of compounds according toFormula I. Such products may result from, for example, the oxidation,reduction, hydrolysis, amidation, esterification, and like processesprimarily due to enzymatic activity upon administration of a compound ofthe invention. Accordingly, the invention includes compounds that areproduced as by-products of enzymatic or non-enzymatic activity on aninventive compound following the administration of such a compound to amammal for a period of time sufficient to yield a metabolic product.Metabolic products, particularly pharmaceutically active metabolites aretypically identified by administering a radiolabeled compound of theinvention in a detectable dose to a subject, such as rat, mouse, guineapig, monkey, or human, for a sufficient period of time during whichmetabolism occurs, and isolating the metabolic products from urine,blood or other biological samples that are obtained from the subjectreceiving the radiolabeled compound.

The invention also provides pharmaceutically acceptable salt forms ofFormula I compounds. Encompassed within the scope of the invention areboth acid and base addition salts that are formed by contacting apharmaceutically suitable acid or a pharmaceutically suitable base witha compound of the invention.

To this end, a “pharmaceutically acceptable acid addition salt” refersto those salts which retain the biological effectiveness and propertiesof the free bases, which are not biologically or otherwise undesirable,and which are formed with inorganic acids such as, but are not limitedto, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

Similarly, a “pharmaceutically acceptable base addition salt” refers tothose salts which retain the biological effectiveness and properties ofthe free acids, which are not biologically or otherwise undesirable.These salts are prepared by addition of an inorganic base or an organicbase to the free acid. Salts derived from inorganic bases include, butare not limited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

Compounds of the invention or their pharmaceutically acceptable saltsmay contain one or more asymmetric centers and may thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

The term “tautomer” refers to a proton shift from one atom of a moleculeto another atom of the same molecule.

The inventive compounds are synthesized using conventional syntheticmethods, and more specifically using the general methods noted below.

Pharmaceutical Formulations

In one embodiment, a compounds according Formulae I are formulated aspharmaceutically acceptable compositions that contain a Formulae Icompound in an amount effective to treat a particular disease orcondition of interest upon administration of the pharmaceuticalcomposition to a mammal. Pharmaceutical compositions in accordance withthe present invention can comprise a Formulae I compound in combinationwith a pharmaceutically acceptable carrier, diluent or excipient.

In this regard, a “pharmaceutically acceptable carrier, diluent orexcipient” includes without limitation any adjuvant, carrier, excipient,glidant, sweetening agent, diluent, preservative, dye/colorant, flavorenhancer, surfactant, wetting agent, dispersing agent, suspending agent,stabilizer, isotonic agent, solvent, or emulsifier which has beenapproved by the United States Food and Drug Administration as beingacceptable for use in humans or domestic animals.

Further, a “mammal” includes humans and both domestic animals such aslaboratory animals and household pets (e.g., cats, dogs, swine, cattle,sheep, goats, horses, rabbits), and non-domestic animals such aswildlife and the like.

The pharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, buccal, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. Pharmaceutical compositions of the invention areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy andScience, 2000). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease or condition of interest in accordance with the teachingsof this invention.

A pharmaceutical composition of the invention may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral syrup, injectable liquid or an aerosol, which is useful in, forexample, inhalatory administration. When intended for oraladministration, the pharmaceutical composition is preferably in eithersolid or liquid form, where semi-solid, semi-liquid, suspension and gelforms are included within the forms considered herein as either solid orliquid.

As a solid composition for oral administration the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample, a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, forexample, an elixir, syrup, solution, emulsion or suspension. The liquidmay be for oral administration or for delivery by injection, as twoexamples. When intended for oral administration, preferred compositioncontain, in addition to the present compounds, one or more of asweetening agent, preservatives, dye/colorant and flavor enhancer. In acomposition intended to be administered by injection, one or more of asurfactant, preservative, wetting agent, dispersing agent, suspendingagent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.

The pharmaceutical composition of the invention may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device.

The pharmaceutical composition of the invention may be intended forrectal administration, in the form, for example, of a suppository, whichwill melt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formmay include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention may consist of dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One skilled in the art, without undueexperimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention may be prepared by anymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

In certain embodiments a pharmaceutical composition comprising acompound of Formula I is administered to a mammal in an amountsufficient to inhibit eIF4A activity upon administration, and preferablywith acceptable toxicity to the same. eIF4A activity of Formula Icompounds can be determined by one skilled in the art, for example, asdescribed in the Examples below. Appropriate concentrations and dosagescan be readily determined by one skilled in the art.

Therapeutic Use

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy.

“Effective amount” or “therapeutically effective amount” refers to thatamount of a compound of the invention which, when administered to amammal, preferably a human, is sufficient to effect treatment, asdefined below, of a eIF4A related condition or disease in the mammal,preferably a human. The amount of a compound of the invention whichconstitutes a “therapeutically effective amount” will vary depending onthe compound, the condition and its severity, the manner ofadministration, and the age of the mammal to be treated, but can bedetermined routinely by one of ordinary skill in the art having regardto his own knowledge and to this disclosure.

Compounds of the invention or pharmaceutically acceptable salt thereofmay also be administered simultaneously with, prior to, or afteradministration of one or more other therapeutic agents. Such combinationtherapy includes administration of a single pharmaceutical dosageformulation which contains a compound of the invention and one or moreadditional active agents, as well as administration of the compound ofthe invention and each active agent in its own separate pharmaceuticaldosage formulation. For example, a compound of the invention and theother active agent can be administered to the patient together in asingle oral dosage composition such as a tablet or capsule, or eachagent administered in separate oral dosage formulations. Where separatedosage formulations are used, the compounds of the invention and one ormore additional active agents can be administered at essentially thesame time, i.e., concurrently, or at separately staggered times, i.e.,sequentially; combination therapy is understood to include all theseregimens.

In certain embodiments the disclosed compounds are useful for inhibitingthe activity of eIF4A and/or can be useful in analyzing eIF4A signalingactivity in model systems and/or for preventing, treating, orameliorating a symptom associated with a disease, disorder, orpathological condition involving eIF4A, preferably one afflictinghumans. A compound which inhibits the activity of eIF4A will be usefulin preventing, treating, ameliorating, or reducing the symptoms orprogression of diseases of uncontrolled cell growth, proliferationand/or survival, inappropriate cellular immune responses, orinappropriate cellular inflammatory responses or diseases which areaccompanied with uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune responses, or inappropriatecellular inflammatory responses, particularly in which the uncontrolledcell growth, proliferation and/or survival, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses ismediated by eIF4A, such as, for example, haematological tumors, solidtumors, and/or metastases thereof, including leukaemias andmyelodysplastic syndrome, Waldenstrom macroglobulinemia, and malignantlymphomas, for example, B-cell lymphoma, T-cell lymphoma, hairy celllymphoma, Hodgkin's lymphoma, non-Hodgin's lymphoma, and Burkitt'slymphoma, head and neck tumors including brain tumors and brainmetastases, tumors of the thorax including non-small cell and small celllung tumors, gastrointestinal tumors, endocrine tumors, mammary andother gynecological tumors, urological tumors including renal, bladderand prostate tumors, skin tumors, and sarcomas, and/or metastasesthereof.

Furthermore, the inventive compounds and their pharmaceuticalcompositions are candidate therapeutics for the prophylaxis and/ortherapy of cytokine related diseases, such as inflammatory diseases,allergies, or other conditions associated with proinflammatorycytokines. Exemplary inflammatory diseases include without limitation,chronic or acute inflammation, inflammation of the joints such aschronic inflammatory arthritis, rheumatoid arthritis, psoriaticarthritis, osteoarthritis, juvenile rheumatoid arthritis, Reiter'ssyndrome, rheumatoid traumatic arthritis, rubella arthritis, acutesynovitis and gouty arthritis; inflammatory skin diseases such assunburn, psoriasis, erythrodermic psoriasis, pustular psoriasis, eczema,dermatitis, acute or chronic graft formation, atopic dermatitis, contactdermatitis, urticaria and scleroderma; inflammation of thegastrointestinal tract such as inflammatory bowel disease, Crohn'sdisease and related conditions, ulcerative colitis, colitis, anddiverticulitis; nephritis, urethritis, salpingitis, oophoritis,endomyometritis, spondylitis, systemic lupus erythematosus and relateddisorders, multiple sclerosis, asthma, meningitis, myelitis,encephalomyelitis, encephalitis, phlebitis, thrombophlebitis,respiratory diseases such as asthma, bronchitis, chronic obstructivepulmonary disease (COPD), inflammatory lung disease and adultrespiratory distress syndrome, and allergic rhinitis; endocarditis,osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumaticendocarditis, rheumatic myocarditis, rheumatic mitral valve disease,rheumatic aortic valve disease, prostatitis, prostatocystitis,spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis,myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis orbursitis, gout, pseudo gout, vasculitides, inflammatory diseases of thethyroid selected from granulomatous thyroiditis, lymphocyticthyroiditis, invasive fibrous thyroiditis, acute thyroiditis;Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's phenomenon,Sjogren's syndrome, neuroinflammatory disease, sepsis, conjunctivitis,keratitis, iridocyclitis, optic neuritis, otitis, lymphoadenitis,nasopaharingitis, sinusitis, pharyngitis, tonsillitis, laryngitis,epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis.oesophagitis, gastritis, peritonitis, hepatitis, cholelithiasis,cholecystitis, glomerulonephritis, goodpasture's disease, crescenticglomerulonephritis, pancreatitis, endomyometritis, myometritis,metritis, cervicitis, endocervicitis, exocervicitis, parametritis,tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,pneumoconiosis, pyresis, inflammatory polyarthropathies, psoriatricarthropathies, intestinal fibrosis, bronchiectasis and enteropathicarthropathies.

Yet further, the inventive compounds and their pharmaceuticalcompositions are candidate therapeutics for the prophylaxis and/ortherapy of fibrotic diseases, such as various forms of fibrosis,fibromas or any disease giving rise to fibrosis whether as a main or asecondary symptom. Exemplary fibrotic diseases include withoutlimitation, viral hepatitis, hepatic fibrosis, liver fibrosis, renalfibrosis, schistosomiasis, steatohepatitis (alcoholic or non-alcoholic(NASH)), cirrhosis, idiopathic pulmonary fibrosis (IPF), systemicsclerosis (scleroderma), nephrogenic systemic fibrosis (NSF), diabetes,untreated hypertension, heart attack, hypertension, atherosclerosis,restenosis, macular degeneration, retinal and vitreal retinopathy,keloids, hypertrophic scars, Crohn's disease and Alzheimer's disease.

Although inflammation is the unifying pathogenic process of thesediseases, current therapies only treat the symptoms of the disease andnot the underlying cause of inflammation. The compositions of thepresent invention are useful for the treatment and/or prophylaxis ofinflammatory diseases and related complications and disorders.

Accordingly, certain embodiments are directed to a method for treating aeIF4A dependent condition in a mammal in need thereof, the methodcomprising administering an effective amount of a pharmaceuticalcomposition as described above (i.e., a pharmaceutical compositioncomprising any one or more compounds of Formula I) to a mammal.

As described above deregulation of protein synthesis is a common eventin human cancers. A key regulator of translational control is eIF4Ewhose activity is a key determinant of tumorigenicity. Inhibitors ofeIF4A are suitable candidate therapeutics for treating cellproliferative disorders such as cancer. A wide variety of cancers,including solid tumors, lymphomas and leukemias, are amenable to thecompositions and methods disclosed herein. Types of cancer that may betreated include, but are not limited to: adenocarcinoma of the breast,prostate, and colon; all forms of bronchogenic carcinoma of the lung;myeloid; melanoma; hepatoma; neuroblastoma; papilloma; apudoma;choristoma; branchioma; malignant carcinoid syndrome; carcinoid heartdisease; and carcinoma (e.g., Walker, basal cell, basosquamous,Brown-Pearce, ductal, Ehrlich tumor, Krebs 2, merkel cell, mucinous,non-small cell lung, oat cell, papillary, scirrhous, bronchiolar,bronchogenic, squamous cell, and transitional cell). Additional types ofcancers that may be treated include: histiocytic disorders; leukemia;histiocytosis malignant; Hodgkin's disease; immunoproliferative small;non-Hodgkin's lymphoma; T-cell lymphoma, B-cell lymphoma, hairy celllymphoma, Burkitt's lymphoma, plasmacytoma; reticuloendotheliosis;melanoma; chondroblastoma; chondroma; chondrosarcoma; fibroma;fibrosarcoma; giant cell tumors; histiocytoma; lipoma; liposarcoma;mesothelioma; myxoma; myxosarcoma; osteoma; osteosarcoma; chordoma;craniopharyngioma; dysgerminoma; hamartoma; mesenchymoma; mesonephroma;myosarcoma; ameloblastoma; cementoma; odontoma; teratoma; thymoma;trophoblastic tumor.

Other cancers that can be treated using the inventive compounds includewithout limitation adenoma; cholangioma; cholesteatoma; cyclindroma;cystadenocarcinoma; cystadenoma; granulosa cell tumor; gynandroblastoma;hepatoma; hidradenoma; islet cell tumor; Leydig cell tumor; papilloma;sertoli cell tumor; theca cell tumor; leimyoma; leiomyosarcoma;myoblastoma; myomma; myosarcoma; rhabdomyoma; rhabdomyosarcoma;ependymoma; ganglioneuroma; glioma; medulloblastoma; meningioma;neurilemmoma; neuroblastoma; neuroepithelioma; neurofibroma; neuroma;paraganglioma; paraganglioma nonchromaffin.

In one embodiment the inventive compounds are candidate therapeuticagents for the treatment of cancers such as angiokeratoma; angiolymphoidhyperplasia with eosinophilia; angioma sclerosing; angiomatosis;glomangioma; hemangioendothelioma; hemangioma; hemangiopericytoma;hemangiosarcoma; lymphangioma; lymphangiomyoma; lymphangiosarcoma;pinealoma; carcinosarcoma; chondrosarcoma; cystosarcoma phyllodes;fibrosarcoma; hemangiosarcoma; leiomyosarcoma; leukosarcoma;liposarcoma; lymphangiosarcoma; myosarcoma; myxosarcoma; ovariancarcinoma; rhabdomyosarcoma; sarcoma; neoplasms; nerofibromatosis; andcervical dysplasia.

In a particular embodiment the present disclosure provides methods fortreating colon cancer, colorectal cancer, gastric cancer, thyroidcancer, lung cancer, leukemia, acute myeloid leukemia, pancreaticcancer, melanoma, multiple melanoma, brain cancer, primary and secondaryCNS cancer, including malignant glioma and glioblastoma, renal cancer,prostate cancer, including castration-resistant prostate cancer, ovariancancer, or breast cancer, including triple negative, HER2 positive, andhormone receptor positive breast cancers. According to such a method, atherapeutically effective amount of at least one compound according toFormula I or a stereoisomer, tautomer or pharmaceutically acceptablesalt thereof can be administered to a subject who has been diagnosedwith a cell proliferative disease, such as a cancer. Alternatively, apharmaceutical composition comprising at least one compound according toFormula I or a stereoisomer, tautomer or pharmaceutically acceptablesalt thereof can be administered to a subject who has been diagnosedwith cancer.

In certain embodiments the compounds in accordance with the inventionare administered to a subject with cancer in conjunction with otherconventional cancer therapies such as radiation treatment or surgery.Radiation therapy is well-known in the art and includes X-ray therapies,such as gamma-irradiation, and radiopharmaceutical therapies.

In certain embodiments the inventive eIF4A inhibitor compounds are usedwith at least one anti-cancer agent. Anti-cancer agents includechemotherapeutic drugs. A chemotherapeutic agent includes, but is notlimited to, an inhibitor of chromatin function, a topoisomeraseinhibitor, a microtubule inhibiting drug, a DNA damaging agent, anantimetabolite (such as folate antagonists, pyrimidine analogs, purineanalogs, and sugar-modified analogs), a DNA synthesis inhibitor, a DNAinteractive agent (such as an intercalating agent), and a DNA repairinhibitor.

Illustrative chemotherapeutic agents include, without limitation, thefollowing groups: anti-metabolites/anti-cancer agents, such aspyrimidine analogs (5-fluorouracil, floxuridine, capecitabine,gemcitabine and cytarabine) and purine analogs, folate antagonists andrelated inhibitors (mercaptopurine, thioguanine, pentostatin and2-chlorodeoxyadenosine (cladribine)); antiproliferative/antimitoticagents including natural products such as vinca alkaloids (vinblastine,vincristine, and vinorelbine), microtubule disruptors such as taxane(paclitaxel, docetaxel), vincristin, vinblastin, nocodazole, epothilonesand navelbine, epidipodophyllotoxins (etoposide, teniposide), DNAdamaging agents (actinomycin, amsacrine, anthracyclines, bleomycin,busulfan, camptothecin, carboplatin, chlorambucil, cisplatin,cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin,epirubicin, hexamethylmelamineoxaliplatin, iphosphamide, melphalan,merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, plicamycin,procarbazine, taxol, taxotere, temozolamide, teniposide,triethylenethiophosphoramide and etoposide (VP 16)); antibiotics such asdactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin),idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin; enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents;antiproliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates-busulfan, nitrosoureas (carmustine (BCNU)and analogs, streptozocin), trazenes-dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate); platinum coordination complexes (cisplatin,carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide;hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide,nilutamide) and aromatase inhibitors (letrozole, anastrozole);anticoagulants (heparin, synthetic heparin salts and other inhibitors ofthrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory agents; antisecretory agents(breveldin); immunosuppressives (cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), azathioprine, mycophenolate mofetil);anti-angiogenic compounds (TNP470, genistein) and growth factorinhibitors (vascular endothelial growth factor (VEGF) inhibitors,fibroblast growth factor (FGF) inhibitors); angiotensin receptorblocker; nitric oxide donors; anti-sense oligonucleotides; antibodies(trastuzumab, rituximab); chimeric antigen receptors; cell cycleinhibitors and differentiation inducers (tretinoin); mTOR inhibitors,topoisomerase inhibitors (doxorubicin (adriamycin), amsacrine,camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin,etoposide, idarubicin, irinotecan (CPT-11) and mitoxantrone, topotecan,irinotecan), corticosteroids (cortisone, dexamethasone, hydrocortisone,methylpednisolone, prednisone, and prenisolone); growth factor signaltransduction kinase inhibitors; mitochondrial dysfunction inducers,toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetellapertussis adenylate cyclase toxin, or diphtheria toxin, and caspaseactivators; and chromatin disruptors.

In certain embodiments an eIF4A inhibitor in accordance with the presentinvention is used simultaneously, in the same formulation or in separateformulations, or sequentially with an additional agent(s) as part of acombination therapy regimen.

eIF4A inhibitors according to Formula I including their correspondingsalts and pharmaceutically acceptable compositions of Formula Icompounds are also effective as therapeutic agents for treating orpreventing cytokine mediated disorders, such as inflammation in apatient, preferably in a human. In one embodiment, a compound orcomposition in accordance with the invention is particularly useful fortreating or preventing a disease selected from chronic or acuteinflammation, chronic inflammatory arthritis, rheumatoid arthritis,psoriasis, COPD, inflammatory bowel disease, septic shock, Crohn'sdisease, ulcerative colitis, multiple sclerosis and asthma.

The inventive compounds their corresponding salts and pharmaceuticallyacceptable compositions are candidate therapeutics for treating brainrelated disorders which include without limitation autism, FragileX-syndrome, Parkinson's disease and Alzheimer's disease. Treatment iseffected by administering to a subject in need of treatment a Formula Icompound, its pharmaceutically acceptable salt form, or apharmaceutically acceptable composition of a Formula I compound or itssalt.

The invention also supports the use of the inventive compounds or apharmaceutically acceptable formulation of the inventive compound as aninhibitor of eIF4A activity. Such inhibition is achieved by contacting acell expressing eIF4A with a compound or a pharmaceutically acceptableformulation, to lower or inhibit eIF4A activity, to provide therapeuticefficacy for a eIF4A dependent condition in a mammal in need thereof.

Therapeutically effective dosages of a compound according to Formula Ior a composition of a Formula I compound will generally range from about1 to 2000 mg/day, from about 10 to about 1000 mg/day, from about 10 toabout 500 mg/day, from about 10 to about 250 mg/day, from about 10 toabout 100 mg/day, or from about 10 to about 50 mg/day. Thetherapeutically effective dosages may be administered in one or multipledoses. It will be appreciated, however, that specific doses of thecompounds of the invention for any particular patient will depend on avariety of factors such as age, sex, body weight, general healthcondition, diet, individual response of the patient to be treated, timeof administration, severity of the disease to be treated, the activityof particular compound applied, dosage form, mode of application andconcomitant medication. The therapeutically effective amount for a givensituation will readily be determined by routine experimentation and iswithin the skills and judgment of the ordinary clinician or physician.In any case the compound or composition will be administered at dosagesand in a manner which allows a therapeutically effective amount to bedelivered based upon patient's unique condition.

General Synthetic Methods General Method (“GM”) 1:

The formation of I (X is O) is accomplished by a multi-step syntheticsequence starting with compound II. Condensation of compounds II andIII, followed by treatment with hydrogen peroxide and sodium hydroxidein ethanol gives intermediate V. Hydroxyflavone V is submitted to asequence of photocycloaddition, ketol rearrangement, and directedstereoselective reduction to give a diastereoisomeric mixture offlavagline IX and X. Deprotection and/or further functional groupmanipulation, if necessary, generate compound I (X is O). Compound I inits enantiomeric pure form is finally obtained via chiral HPLCseparation.

General Method 2:

Alternatively, the formation of compound I (X is as defined in thespecification) is accomplished by the synthetic sequence describedimmediately above. In this synthesis, Michael addition of compound XI tocompound XII yields the desired syn-arranged product XIII. Aldehyde XIIIis subjected to trimethylsilyl cyanide to yield the cyanohydrin XIV.Formation of acyloin XV is initiated by addition of lithiumdiisopropylamide to XIV, followed by deprotection of the resultingmixture with potassium carbonate. Treatment of XV with excess of Stilesreagent in dimethylformamide at 100° C. results in the formation of theketoester XVI. Deprotection and/or further functional groupmanipulation, if necessary, generates compound I. Compound I in itsenantiomeric pure form is finally obtained via chiral HPLC separation.

General Method 3:

The formation of I (R^(3a)═H, and R^(3b)═—CH₂NR⁹ ₂) is accomplished by amulti-step synthetic sequence starting with compound XVII. Esterhydrolysis of compounds XVII, followed by amide coupling with NHR⁹ ₂gives intermediate XIX. Amide XIX is reduced with borane upon heating toprovide amine XX. Deprotection and/or further functional groupmanipulation, if necessary, generate compound I (R^(3a)═H, andR^(3b)═—CH₂NR⁹ ₂). Compound I in its enantiomeric pure form is finallyobtained via chiral HPLC separation.

General Method 4:

The formation of I (R^(3a), R^(3b) and R^(4b)═H, and R^(4a)═—CH₂NR⁹ ₂)is accomplished by a multi-step synthetic sequence starting withcompound XVII. Compound XVII is treated with methanesulfonyl chloride inpyridine to form mesylate XXI. Stereoselective replacement of themesylate moiety with a cyano group is accomplished with potassiumcyanide. The resulting cyano ester XXII is hydrolyzed, followed byBarton's radical decarboxylation to produce nitrile XXIV. The cyanomoiety is reduced to primary amine with lithium aluminum hydride.Functionalization of the primary amino group to generate amine XXVI isaccomplished via standard alkylation, imine formation/reduction or amideformation/reduction methods. Deprotection and/or further functionalgroup manipulation, if necessary, generate compound I (R^(3a), R^(3b)and R^(4b)═H, and R^(4a)═—CH₂NR⁹ ₂). Compound I in its enantiomeric pureform is finally obtained via chiral HPLC separation.

General Method 5:

The formation of I (R^(3a) and R^(4b)═H, R^(3b)═—CH₂OH andR^(4a)═—CH₂NR⁹ ₂) is accomplished by a multi-step synthetic sequencestarting with compound XXII. Compound XXII is reduced with lithiumaluminum hydride to generate compound XXVII. Functionalization of theprimary amino group to generate amine XXVIII is accomplished viastandard alkylation, imine formation/reduction or amideformation/reduction methods. Deprotection and/or further functionalgroup manipulation, if necessary, generate compound I (R^(3a) andR^(4b)═H, R^(3b)CH₂OH and R^(4a)═—CH₂NR⁹ ₂). Compound I in itsenantiomeric pure form is finally obtained via chiral HPLC separation.

General Method 6:

The formation of I (R^(3a) or R^(3b)═—SO₂NR⁹R⁹) is accomplished by amulti-step synthetic sequence starting with hydroxyflavone V. V issubmitted to a sequence of photocycloaddition, ketol rearrangement, anddirected stereoselective reduction to give a diastereoisomeric mixtureof flavagline XXXI and XXXII. Deprotection and/or further functionalgroup manipulation, if necessary, generates compound I (R^(3a) orR^(3b)═SO₂NR⁹R⁹). Compound I in its enantiomeric pure form is finallyobtained via chiral HPLC separation.

General Method 7:

The formation of compound I (R^(3a)═H and R^(3b)═—SO₂R⁹) is accomplishedby a multi-step synthetic sequence starting with compound XXXIII. XXXIIIis submitted to sodium sulfonate XXXIIIa in the presence of copper(II)bromide and 1,8-diazabicyclo[5.4.0]undec-7-ene to give XXXIV. XXXIV isreduced to give XXXV via sodium triacetylborohydride. Deprotectionand/or further functional group manipulation, if necessary, generatescompound I (R^(3a)═H and R^(3b)═SO₂R⁹). Compound I in its enantiomericpure form is finally obtained via chiral HPLC separation.

Compound I (R^(3a)═H and R^(3b)═—SO₂R⁹) can also be used to formcompound I (R^(3a)═H and R^(3b)═—SO₂NR⁹R⁹) using conventional methodsknown in the chemical art.

General Method 8:

The formation of compound I (R^(3a)═H and R^(3b)═—C(CH₃)₂NR⁹ ₂) isaccomplished by a multi-step synthetic sequence starting with compoundXXXIII. XXXIII is treated with lithium diisopropylamide followed bydimethyl acetal XXXIIIb to generate enone XXXVI. XXXVI is then treatedwith a nucleophile to give the Michael adduct XXXVII. The ketone groupis reduced via sodium triacetylborohydride to produce compound XXXVIII.Deprotection and/or further functional group manipulation, if necessary,generates compound I (R^(3a)═H and R^(3b)C(CH₃)₂NR⁹ ₂). Compound I inits enantiomeric pure form is finally obtained via chiral HPLCseparation.

General Method 9:

The formation of compound I (R^(3a)═H and R^(3b)═—C(CH₂)₂NR⁹ ₂) isaccomplished by a multi-step synthetic sequence starting with compoundXXXIII. The trimethylsilyl enol ether of XXXIII reacts with compoundXXXIXa in the presence of titanium tetrachloride to generate compoundXL. XL is reduced via sodium triacetylborohydride to produce compoundXLI.

Deprotection and/or further functional group manipulation, if necessary,generates compound I (R^(3a)═H and R^(3b)═C(CH₂)₂NR⁹ ₂). Compound I inits enantiomeric pure form is finally obtained via chiral HPLCseparation.

General Method 10:

The formation of compound I (R^(3a)═H and R^(3b)═—C(CH₂OCH₂)NHR⁹) isaccomplished by a multi-step synthetic sequence starting with compoundXXXIII. The enolate of XXXIII reacts with compound XXXIIIc to generatecompound XLII. XLII is reduced via sodium triacetylborohydride toproduce compound XLIII. Deprotection and/or further functional groupmanipulation, if necessary, generates compound I (R^(3a)═H andR^(3b)═C(CH₂OCH₂)NHR⁹). Compound I in its enantiomeric pure form isfinally obtained via chiral HPLC separation.

General Method 11:

The formation of compound L is accomplished by a multi-step syntheticsequence starting with compound XVIII. One-carbon chain extention ofXVIII via standard procedures generates ester XLIV. XLIV is oxidizedfollowed by treatment with ylide XLVa to produce olefin XLVI. Reductionof the olefin followed by Dieckmann condensation gives rise to compoundXLVIII. Decarboxylation of XLVIII followed by reductive aminationgenerates compound L. Compound L in its diastereomeric and enantiomericpure form is finally obtained via reverse phase HPLC and chiral HPLCseparation.

General Method 12:

The formation of compound I (R^(4a)═—CH₂NR⁹ ₂ and R^(4b)═OH) isaccomplished by a multi-step synthetic sequence starting with compoundXXXIII. XXXIII is converted to olefin LII followed by dihydroxylation inthe presence of osmium tetroxide to generate LIII. The primary hydroxylgroup of LIII is selectively oxidized, followed by reductive aminationto yield amine LV. Deprotection and/or further functional groupmanipulation, if necessary, generates compound I (R^(4a)═—CH₂NR⁹ ₂ andR^(4b)═OH). Compound I in its enantiomeric pure form is finally obtainedvia chiral HPLC separation.

In the above methods, it is understood that if protecting groups areused during the synthesis of intermediates, or if a Formula I compoundcontains one or more protecting groups, then such protecting groups areremoved by methods known in the chemical art. Other functional grouptransformations, such as the conversion of atom X from S to S(O)₂, fromC═O to C═CR⁶R⁷, from NH to N(C₁-C₈)alkyl, and the conversion of anintermediate or a Formula I compound to a pharmaceutically acceptablesalt are carried out using conventional methods known in the chemicalart.

EXAMPLES Example 1Rac-(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-3-methoxy-5a-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 1F)

Synthesis of 3,5-dimethoxypicolinonitrile (2)

To a solution of 3,5-difluoropicolinonitrile (1, 50 g, 0.36 mol) inmethanol (80 mL), sodium methoxide (30% in methanol, 150 mL, 0.83 mol)was added. The reaction mixture was refluxed at 100° C. for 12 h. Aftercompletion, the solvent was removed under reduced pressure and the crudewas treated with saturated ammonium chloride solution (50 mL) to getprecipitate. The precipitated solid was filtered, washed with water anddried under vacuum to afford 3,5-dimethoxypicolinonitrile (2) as a whitesolid. Yield: 42 g, 72%; MS (ESI) m/z 165.23[M+1]⁺.

Synthesis of 1-(3,5-dimethoxypyridin-2-yl)ethan-1-one (3)

To a solution of 3,5-dimethoxypicolinonitrile (2, 42 g, 256 mmol) in drytetrahydrofuran (100 mL) at −20° C., methyl magnesium chloride (255.8mL, 767.53 mmol) was added dropwise over a period of 30 min. Thereaction mass was slowly brought to room temperature and stirred for anadditional 12 h. After completion, the reaction mass was quenched with6M hydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with 1 M sodium hydroxide solution and water, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford 1-(3,5-dimethoxypyridin-2-yl)ethan-1-one (3) as ayellow oil. Yield: 30.0 g, 64.72%; MS (ESI) m/z 181.61[M+1]⁺.

Synthesis of 1-(3,5-dihydroxypyridin-2-yl)ethan-1-one (4)

A sealed tube was charged with 1-(3,5-dimethoxypyridin-2-yl)ethan-1-one(3, 30.0 g, 165.9 mmol) and hydrobromic acid (33% in acetic acid, 300mL) was added and the reaction mixture was heated at 150° C. for 16 h.After completion, volatiles were removed under reduced pressure and thecrude was neutralized to pH ˜8 using 10% sodium hydroxide and ethylacetate (300 mL) was added. The solution was passed through a bed ofcelite and the bed was washed with ethyl acetate (100 mL). The organiclayer was separated from the combined filtrate and dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford 1-(3,5-dihydroxypyridin-2-yl)ethan-1-one (4) as a brown oil.Yield: 9.0 g, 35%; MS (ESI) m/z 152.0[M−1]⁻.

Synthesis of 1-(3-hydroxy-5-methoxypyridin-2-yl)ethan-1-one (5)

To a solution of 1-(3,5-dihydroxypyridin-2-yl)ethan-1-one (4, 9.0 g,58.8 mmol) in acetone (100 mL) at 0° C., potassium carbonate (24.3 g,176.4 mmol) was added followed by addition of methyl iodide. Thereaction mixture was stirred at room temperature for 6 h. Aftercompletion, the solvent was distilled off and water (20 mL) was added.The reaction mass was extracted with 5% methanol in dichloromethane (100mL). The organic layer was washed with water and brine, dried overanhydrous sodium sulfate, filtered and concentrated to afford1-(3-hydroxy-5-methoxypyridin-2-yl)ethan-1-one (5) as an off-whitesolid. Yield: 8.5 g, crude.

Synthesis of(E)-1-(3-hydroxy-5-methoxypyridin-2-yl)-3-(4-methoxyphenyl)prop-2-en-1-one(7)

To a solution of 1-(3-hydroxy-5-methoxypyridin-2-yl)ethan-1-one (5, 8.5g, 50.8 mmol) and sodium hydroxide (6.1 g, 152.0 mmol) in methanol (50mL), 4-methoxybenzaldehyde (6, 6.9 g, 50.8 mmol) was added. The reactionwas heated to reflux for 4 h. After completion, the reaction mass wascooled to room temperature. The solid was filtered, washed with waterand then dried under vacuum to afford(E)-1-(3-hydroxy-5-methoxypyridin-2-yl)-3-(4-methoxyphenyl)prop-2-en-1-one(7) as a yellow solid. Yield: 9.0 g, crude; MS (ESI) m/z 286.23[M+1]⁺.

Synthesis of3-hydroxy-7-methoxy-2-(4-methoxyphenyl)-4H-pyrano[3,2-b]pyridin-4-one(8)

To a solution of(E)-1-(3-hydroxy-5-methoxypyridin-2-yl)-3-(4-methoxyphenyl)prop-2-en-1-one(7, 9.0 g, 31.5 mmol) and sodium hydroxide (3.78 g, 94.7 mmol) inmethanol (50 mL) at 0° C., hydrogen peroxide (10.73 mL, 94.7 mmol) wasadded. The reaction mass was stirred for 6 h at room temperature(exotherm was observed). After completion, the reaction mass was cooledand neutralized to pH ˜7 by the addition of 6 M hydrogen chloride. Theprecipitated solid was filtered and dried under vacuum to afford of3-hydroxy-7-methoxy-2-(4-methoxyphenyl)-4H-pyrano[3,2-b]pyridin-4-one(8) as a yellow solid. Yield: 3.5 g, 37%; MS (ESI) m/z 452.19[M+1]⁺.

Synthesis of rac-methyl(7S,8S,9R)-9-hydroxy-3-methoxy-6-(4-methoxyphenyl)-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(10)

A solution of3-hydroxy-7-methoxy-2-(4-methoxyphenyl)-4H-pyrano[3,2-b]pyridin-4-one(8, 3.5 g, 11.3 mmol) and methyl cinnamate (9, 19 g, 111.7 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedfor 15 h under 400 watts UV light. After completion, the solvent wasremoved under reduced pressure and the residue was purified over a plugof silica gel eluting the compound with ethyl acetate. The desiredfractions were concentrated under reduced pressure to afford rac-methyl(7S,8S,9R)-9-hydroxy-3-methoxy-6-(4-methoxyphenyl)-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(10). Yield: 3.0 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-8a-hydroxy-3-methoxy-5a-(4-methoxyphenyl)-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(11)

The crude compound rac-methyl(7S,8S,9R)-9-hydroxy-3-methoxy-6-(4-methoxyphenyl)-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(10, 3.0 g)) was suspended in methanol (30 mL) and treated with 25%sodium methoxide in methanol (30 mL). The reaction was heated at 80° C.for 2 h. After completion, the solvent was removed under reducedpressure. The crude was diluted with ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and concentrated under reduced pressure to affordrac-methyl(5aR,6S,7R,8aR)-8a-hydroxy-3-methoxy-5a-(4-methoxyphenyl)-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(11, 3.0 g, crude).

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-3-methoxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(12)

To a solution of sodium triacetoxyborohydride (8.27 g, 3.9 mmol),rac-methyl(5aR,6S,7R,8aR)-8a-hydroxy-3-methoxy-5a-(4-methoxyphenyl)-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(11, 3.0 g, 6.5 mmol) in acetonitrile (50 mL), acetic acid (3.9 g, 66.5mmol) was added. The resulting mixture was stirred for 4 h at roomtemperature. After completion, the reaction mixture was partitionedbetween saturated aqueous sodium bicarbonate solution and ethyl acetate.The organic layer was separated, dried over sodium sulphate, filteredand concentrated under reduced pressure to get the crude. The crude waspurified by silica gel column chromatography eluting with 50% ethylacetate in hexanes. The desired fractions were concentrated to affordrac-methyl(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-3-methoxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(12). Yield: 1.2 g, 39.86%; MS (ESI) m/z 464.29[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-3-methoxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (13)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-3-methoxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(12, 1.2 g, 2.5 mmol) in methanol and water (3:1, 20 mL), lithiumhydroxide (1.49 g, 62.2 mmol) was added and the reaction was stirred for16 h at room temperature. After completion, the reaction mass was cooledto 0° C. and acidified with 1 M hydrochloric acid to pH 2-3. Theprecipitate was filtered and dried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-3-methoxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (13) as an off-white solid. Yield: 0.9 g, 77.33%; MS (ESI) m/z450.28[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-3-methoxy-5a-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 1F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-3-methoxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (13, 0.9 g, 2.0 mmol) in dichloromethane (30 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.15 g, 6.0 mmol),hydroxybenzotriazole (0.8 g, 6.0 mmol) and N,N-diisopropylethylamine(1.55 g, 12.0 mmol) were added and the mixture was stirred for 5 min.Dimethylamine hydrochloride (0.814 g, 10.02 mmol) was then added at thesame temperature and the reaction was stirred for 12 h at roomtemperature. After completion, the reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive the crude. The crude was purified by silica gel columnchromatography eluting with 70-90% ethyl acetate in hexanes to affordrac-(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-3-methoxy-5a-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 1F) as an off-white solid. Yield: 0.077 g, 7.33%; MS (ESI) m/z477.22[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (d, J=2.4 Hz, 1H), 7.20(d, J=2.4 Hz, 1H), 7.09-7.00 (m, 4H), 6.94-6.98 (m, 1H), 6.86 (d, J=7.2Hz, 2H), 6.64 (d, J=9.2 Hz, 2H), 5.61 (s, 1H), 5.05 (d, J=5.2 Hz, 1H),4.84 (t, J=6 Hz, 1H), 4.31 (d, J=13.2 Hz, 1H), 4.09 (dd, J=13.2, 6.4 Hz,1H), 3.86 (s, 3H), 3.61 (s, 3H), 3.22 (s, 3H), 2.74 (s, 3H).

Example 2(5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 2F)

Synthesis of 3,5-bis(benzyloxy)picolinonitrile (2)

To a solution of 3,5-dichloropicolinonitrile (1, 65.0 g, 377.2 mmol) intetrahydrofuran (500 mL) under nitrogen, sodium hydride (27.2 g, 1.13mol) was added at 0° C. The suspension was stirred at room temperaturefor 30 minutes. Benzyl alcohol (81.37 mL, 755 mmol) was added and thereaction was stirred for another 3 h. After completion, the reactionmass was treated with saturated ammonium chloride solution at 0° C. Theresidue was dissolved in ethyl acetate (1000 mL), separated the organiclayer and washed with water (2×200 mL) then with brine (100 mL). Theorganics were separated and dried over anhydrous sodium sulfate beforeconcentration to dryness and triturated with pentane. The precipitatedsolid was filtered and dried under vacuum to afford3,5-bis(benzyloxy)picolinonitrile (2) as an off-white solid. Yield:130.0 g, crude; MS (ESI) m/z 317.21[M+1]⁺.

Synthesis of 1-(3,5-bis(benzyloxy)pyridin-2-yl)ethan-1-one (3)

To a solution of 3,5-bis(benzyloxy)picolinonitrile (2, 70.0 g, 221.5mmol) in dry tetrahydrofuran (500 mL), methyl magnesium bromide (78.37mL, 664.5 mmol) was added dropwise over a period of 30 min at −30° C.The reaction mass was slowly brought to room temperature and stirred for2 h. After completion, the reaction mass was treated with 6M hydrogenchloride and stirred for 2 h. The crude was extracted with ethylacetate. The organic layer was washed with 1M sodium hydroxide solution,water, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to afford1-(3,5-bis(benzyloxy)pyridin-2-yl)ethan-1-one (3) as a yellow oil.Yield: 82.0 g, 93.75%; MS (ESI) m/z 334.16[M+1]⁺.

Synthesis of 1-(3,5-dihydroxypyridin-2-yl)ethan-1-one (4)

To a solution of 1-(3,5-bis(benzyloxy)pyridin-2-yl)ethan-1-one (3, 82.0g, 246.2 mmol) in ethyl acetate (500 mL), palladium hydroxide (34.47 g,246.2 mmol, 50% wet) was added. The reaction was flushed twice withhydrogen gas and stirred at room temperature for 16 h under hydrogenpressure. After completion, the reaction mass was passed through a bedof celite and the filtrate was concentrated under reduced pressure toafford 1-(3,5-dihydroxypyridin-2-yl)ethan-1-one (4) as a brown oil.Yield: 40.0 g, 88.8%; MS (ESI) m/z 152.13[M−1]⁻.

Synthesis of 1-(5-(benzyloxy)-3-hydroxypyridin-2-yl)ethan-1-one (5)

To a solution of 1-(3,5-dihydroxypyridin-2-yl)ethan-1-one (4, 40.0 g,261.4 mmol) in acetone (250 mL), potassium carbonate (72.15 g, 522.8mmol) was added under nitrogen. Benzyl bromide (21.7 mL, 182.9 mmol) wasadded and reaction was stirred for another 3 h. After completion,volatiles were removed under reduced pressure and crude residue wasdissolved in ethyl acetate (200 mL) and washed with water (2×150 mL) andbrine (150 mL). The organics were separated and dried over anhydroussodium sulfate before concentration to dryness and triturated withpentane. The solid was filtered and dried under vacuum to afford1-(5-(benzyloxy)-3-hydroxypyridin-2-yl)ethan-1-one (5) as a brown solid.Yield: 50.0 g, 94.1%; MS (ESI) m/z 244.04[M+1]⁺.

Synthesis of(E)-1-(5-(benzyloxy)-3-hydroxypyridin-2-yl)-3-(4-bromophenyl)prop-2-en-1-one(6)

To a solution of 1-(5-(benzyloxy)-3-hydroxypyridin-2-yl)ethan-1-one (5,50.0 g, 205.6 mmol) and sodium hydroxide (24.69 g, 617.28 mmol) inmethanol (100 mL), 4-bromobenzaldehyde (38.06 g, 205.7 mmol) was addedand the reaction mixture was heated at 85° C. for 2 h. After completion,reaction mass was cooled and solid was filtered, washed with water anddried under vacuum to afford of(E)-1-(5-(benzyloxy)-3-hydroxypyridin-2-yl)-3-(4-bromophenyl)prop-2-en-1-one(6) as a yellow solid. Yield: 50.2 g, 59.64%; MS (ESI) m/z 410.05[M+1]⁺.

Synthesis of7-(benzyloxy)-2-(4-bromophenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one(7)

To a solution of(E)-1-(5-(benzyloxy)-3-hydroxypyridin-2-yl)-3-(4-bromophenyl)prop-2-en-1-one(6, 20.0 g, 48.8 mmol) and sodium hydroxide (13.7 g, 342.2 mmol) inethanol: dichloromethane (1:1, 100 mL), hydrogen peroxide (15.11 mL,684.5 mmol) was added at room temperature. The reaction mass was stirredfor 1 h (exotherm was observed). After completion, reaction mass wascooled and neutralized by addition of 6M hydrogen chloride. Theprecipitated solid was filtered and dried under vacuum to afford7-(benzyloxy)-2-(4-bromophenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one(7) as a yellow solid. Yield: 11.0 g, 53%; MS (ESI) m/z 424.03[M+1]⁺.

Synthesis of rac-methyl(7S,8S,9R)-3-(benzyloxy)-6-(4-bromophenyl)-9-hydroxy-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate (9)

A solution of7-(benzyloxy)-2-(4-bromophenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one(7, 11.0 g, 25.94 mmol) and methyl cinnamate (8, 42.28 g, 259.4 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedunder 400 watts UV light for 15 h. After completion, the solvent wasremoved under reduced pressure and the residue was purified over a plugof silica gel eluting the compound with ethyl acetate. The desiredfractions were concentrated under reduced pressure to afford rac-methyl(7S,8S,9R)-3-(benzyloxy)-6-(4-bromophenyl)-9-hydroxy-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(9, 11.2 g, crude).

Synthesis of rac-methyl(5aR,6S,7R,8aR)-3-(benzyloxy)-5a-(4-bromophenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(10)

The crude compound rac-methyl(7S,8S,9R)-3-(benzyloxy)-6-(4-bromophenyl)-9-hydroxy-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(9, 11.2 g) was suspended in methanol (100 mL) and treated with 25%sodium methoxide in methanol (110 mL) and heated the mixture to 70° C.for 1 h. After completion, the solvent was removed under reducedpressure and crude was treated with ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and concentrated under reduced pressure to affordrac-methyl(5aR,6S,7R,8aR)-3-(benzyloxy)-5a-(4-bromophenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(10). Yield: 11.0 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-bromophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(11)

The above crude compound (10, 11.0 g, crude) was charged to a solutionof sodium triacetoxyborohydride (23.4 g, 112.4 mmol) in acetonitrile (80mL) and acetic acid (11.3 mL, 188.33 mmol) and the resulting mixture wasstirred for 4 h at room temperature. After completion, reaction mixturewas partitioned between saturated aqueous sodium bicarbonate solutionand ethyl acetate. The organic layer was separated, dried over sodiumsulphate and concentrated under reduced pressure to get the crude. Thecrude was purified by silica gel column chromatography eluting with 50%ethyl acetate in hexanes. The desired fractions were concentrated toafford rac-methyl(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-bromophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(11) as a light yellow solid. Yield: 5.7 g, 51.77%; MS (ESI) m/z588.38[M+1]⁺.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(12)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-bromophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(11, 5.0 g, 8.50 mmol) in dimethylformamide, zinc cyanide (6.12 g, 52.0mmol) and zinc (0.055 g, 0.84 mmol) were added at room temperature anddegassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.124 g, 0.169 mmol),tris(dibenzylideneacetone)dipalladium (0.233 g, 0.254 mmol) were addedto the reaction, degassing was continued for 5 min and heated thereaction mixture at 125° C. for 2 h. After completion, the reaction wascooled to room temperature and passed through a bed of celite. Thefiltrate was concentrated and treated with ice-cold water, theprecipitated solid was filtered and dried under vacuum to affordrac-methyl(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(12) as a yellow solid. Yield: 4.4 g, 96.9%; MS (ESI) m/z 535.13[M+1]⁺.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-3,8,8a-trihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(13)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(12, 2.5 g, 4.61 mmol) in ethyl acetate (50 mL), palladium hydroxide(1.66 g, 11.6 mmol, 50% wet) was added at room temperature. The reactionwas flushed with hydrogen gas twice and stirred at room temperature for16 h under hydrogen pressure. After completion, the reaction mass waspassed through a bed of celite and the filtrate was concentrated underreduced pressure to afford rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-3,8,8a-trihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(13) as a brown oil. Yield: 2.01 g, 96.9%; MS (ESI) m/z 443.15[M−1]⁻.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-3-(((trifluoromethyl)sulfonyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(14)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-3,8,8a-trihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(13, 2.01 g, 4.52 mmol) in dichloromethane (100 mL) under nitrogen,N,N-diisopropylethylamine (0.57 g, 4.41 mmol) was added at −78° C.followed by addition of triflic anhydride (0.765 mL, 3.78 mmol). Thereaction was stirred at −78° C. for 45 min. After completion, thereaction mass was treated with saturated sodium bicarbonate solution at0° C. The crude was extracted with dichloromethane (100 mL) and theorganic layer was washed with water (2×50 mL) then with brine (50 mL).The organics were separated and dried over anhydrous sodium sulfatebefore concentration to dryness and triturated with pentane. Theprecipitated solid was filtered and dried under vacuum to affordrac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-3-(((trifluoromethyl)sulfonyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(14) as a yellow solid. Yield: 2.01 g, 77.9%; MS (ESI) m/z 577.1[M+1]⁺.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(15)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-3-(((trifluoromethyl)sulfonyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(14, 2.0 g, 3.48 mmol) in dimethylformamide, zinc cyanide (2.4 g, 20.09mmol) and zinc (0.027 g, 0.418 mmol) were added at room temperature andthe reaction mixture was degassed with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (51.0 mg, 0.006 mmol) andtris(dibenzylideneacetone)dipalladium (95 mg, 0.104 mmol) were added tothe reaction, continued degassing for 5 min and heated the reactionmixture at 125° C. for 2 h. After completion, the reaction was cooled toroom temperature and passed through bed of celite.

Filtrate was concentrated and treated with ice-cold water, theprecipitated solid was filtered and dried under vacuum to affordrac-methyl(5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(15) as a yellow solid. Yield: 1.9 g, crude; MS (ESI) m/z 454.38[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (16)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(15, 1.9 g, 3.29 mmol) in tetrahydrofuran: water (3:1, 12 mL), lithiumhydroxide (0.237 g, 9.87 mmol) was added and the reaction was stirredfor 6 h at room temperature. After completion, the reaction mass wascooled to 0° C. and acidified with 1M hydrogen chloride to pH ˜3. Theprecipitated solid was filtered and dried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (16) as a yellow solid. Yield: 0.55 g, 31%; MS (ESI) m/z438.32[M−1]⁻.

Synthesis of(5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 2F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (16, 0.5 g, 1.1 mmol) in dichloromethane (10 mL), triethylamine(0.46 mL, 3.4 mmol) and dimethylamine.hydrogen chloride (0.139 g, 1.17mmol) were added at 0° C. The mixture was stirred for 5 min and treatedwith propylphosphonic anhydride (0.139 mL, 1.7 mmol, 50% in ethylacetate) at same temperature and the reaction was stirred for 4 h atroom temperature. After completion, reaction mass was diluted withdichloromethane and washed with cold water. The organic layer was driedover sodium sulphate, filtered and concentrated to give the crude. Thecrude was purified by silica gel column chromatography eluting with70-90% ethyl acetate in hexanes to affordrac-(5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(rac-Cpd. No. 2F) as a white solid. The enantiomers were separated bychiral preparative HPLC [chiralpak IB (4.6×250) mm]. Yield: 160 mg, 30%;Peak 1 (Cpd. No. 2F, 35 mg), [α]_(D) −202.0° (c 0.1, CHCl₃), R_(t)=5.99min, ee>99%; MS (ESI) m/z 467.37[M+1]⁺; UPLC: 98.66%; ¹H NMR (400 MHz,DMSO-d₆) δ 8.63 (d, J=1.6 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.5 (d, J=8.4Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.03 (t, J=7.2 Hz, 2H), 6.95 (t, J=8.8Hz, 3H), 6.37 (s, 1H), 5.45 (d, J=5.6 Hz, 1H), 4.76 (t, J=5.2 Hz, 1H),4.70 (d, J=13.2 Hz, 1H), 4.36 (dd, J=13.6, 4.8 Hz, 1H), 3.28 (s, 3H),2.79 (s, 3H); Peak-2 (26 mg), [α]_(D) +242° (c 0.1, CHCl₃), R_(t)=8.46min, ee>95%; MS (ESI) m/z 467.37[M+1]⁺; UPLC: 99.95%; 1H NMR (400 MHz,DMSO-d₆) δ 8.63 (d, J=1.6 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.5 (d, J=8.4Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.03 (t, J=7.2 Hz, 2H), 6.95 (t, J=9.2Hz, 3H), 6.37 (s, 1H), 5.46 (d, J=6 Hz, 1H), 4.76 (t, J=5.2 Hz, 1H),4.70 (d, J=13.2 Hz, 1H), 4.37 (dd, J=13.2, 4.4 Hz, 1H), 3.28 (s, 3H),2.78 (s, 3H).

Example 3(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 3F)

Synthesis of(E)-3-(4-bromophenyl)-1-(5-chloro-3-hydroxypyridin-2-yl)prop-2-en-1-one(2)

To a solution of 1-(5-chloro-3-hydroxypyridin-2-yl)ethan-1-one (1, 10.0g, 58.47 mmol) and sodium hydroxide (7.0 g, 175.0 mmol) in methanol (100mL), 4-bromobenzaldehyde (10.75 g, 58.47 mmol) was added and thereaction heated to reflux for 30 minutes. After completion, reactionmass was cooled and solid was filtered, washed with water and driedunder high vacuum to afford of(E)-3-(4-bromophenyl)-1-(5-chloro-3-hydroxypyridin-2-yl)prop-2-en-1-one(2) as a yellow solid. Yield: 12.0 g, 63%; MS (ESI) m/z 338.95[M+1]⁺.

Synthesis of2-(4-bromophenyl)-7-chloro-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one (3)

To a solution of(E)-3-(4-bromophenyl)-1-(5-chloro-3-hydroxypyridin-2-yl)prop-2-en-1-one(12.0 g, 35.3 mmol) and sodium hydroxide (10.0 g, 249.3 mmol) in ethanol(120 mL) and dichloromethane (40 mL), hydrogen peroxide (8.97 mL, 94.7mmol) was added at room temperature. The reaction mass was stirred for 1h at room temperature (exotherm was observed). After completion,reaction mass was cooled and neutralized to pH ˜7 by addition of 6Mhydrogen chloride. The precipitated solid was filtered and dried undervacuum to afford2-(4-bromophenyl)-7-chloro-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one (3)as a pale yellow solid. Yield: 4.0 g, 33%; MS (ESI) m/z 354.10[M+1]⁺.

Synthesis of rac-methyl(7S,8S,9R)-6-(4-bromophenyl)-3-chloro-9-hydroxy-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(5)

A solution of2-(4-bromophenyl)-7-chloro-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one (3,4.0 g, 11.39 mmol) and methyl cinnamate (4, 18.46 g, 113.9 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedunder 400 watts UV light for 15 h. After completion, the solvent wasremoved under reduced pressure and the residue was purified over a plugof silica gel eluting the compound with ethyl acetate. The desiredfractions were concentrated under reduced pressure to afford rac-methyl(7S,8S,9R)-6-(4-bromophenyl)-3-chloro-9-hydroxy-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(5, 6.0 g, crude).

Synthesis of rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(6)

The crude compound rac-methyl(7S,8S,9R)-6-(4-bromophenyl)-3-chloro-9-hydroxy-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(5, 6.0 g) was suspended in methanol (30 mL) and treated with 25% sodiummethoxide in methanol (30 mL) and heated the mixture to 70° C. for 1 h.After completion, the solvent was removed under reduced pressure andcrude was treated with ammonium chloride solution and extracted withethyl acetate. The organic phase was separated, dried over sodiumsulphate and concentrated under reduced pressure to afford rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(6, 5.0 g, crude).

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7)

The above crude compound (6, 5.0 g, 9.74 mmol) was charged to a solutionof sodium triacetoxyborohydride (12.6 g, 58.4 mmol) in acetonitrile (30mL) and acetic acid (3.6 mL, 97.2 mmol) and the resulting mixture wasstirred for 4 h at room temperature. After completion, reaction mixturewas partitioned between saturated aqueous sodium bicarbonate solutionand ethyl acetate. The organic layer was separated, dried over sodiumsulphate and concentrated under reduced pressure to get the crude. Thecrude was purified by silica gel column chromatography eluting with 50%ethyl acetate in hexanes. The desired fractions were concentrated underreduced pressure to afford rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7) as an off-white solid. Yield: 3.3 g, 66%; MS (ESI) m/z 516.01[M−1]⁻.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (8)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7, 3.3 g, 6.4 mmol) in methanol:water (3:1, 11 mL), lithium hydroxide(3.68 g, 153.6 mmol) was added and the reaction was stirred for 3 h atroom temperature. After completion, the reaction mass was cooled to 0°C. and acidified with 5M hydrogen chloride to pH ˜3. The solidprecipitated was filtered and dried under high vacuum to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (8) as an off-white solid. Yield: 3.2 g, crude; MS (ESI) m/z502.02[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(9)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (8, 3.2 g, 6.39 mmol) in dichloromethane (30 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrogen chloride (3.6 g,19.16 mmol), hydroxybenzotriazole (2.8 g, 19.16 mmol) andN,N-diisopropylethylamine (7.3 mL, 41.9 mmol) were added at 0° C. andstirred the mixture for 5 min. Dimethylamine.hydrogen chloride (2.8 g,34.9 mmol) was then added at same temperature and the reaction wasstirred for 12 h at room temperature. After completion, reaction masswas diluted with dichloromethane and washed with cold water. The organiclayer was separated and dried over sodium sulphate, filtered andconcentrated to give crude. The crude was purified by silica gel columnchromatography eluting with 70-90% ethyl acetate in hexanes to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(9) as a white solid. Yield: 2.9 g, 76%; MS (ESI) m/z 529.05[M+1]⁺.

Synthesis of(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 3F)

To a solution of(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(9, 1.5 g, 2.84 mmol) in dimethylformamide (25 mL), zinc cyanide (6.0 g,17.0 mmol) and zinc (0.022 g, 0.34 mmol) were added and degassed themixture with argon for 15 min. 1,1′-Bis(diphenylphosphino)ferrocene(0.041 g, 0.056 mmol), tris(dibenzylideneacetone)dipalladium (0.078 g,0.085 mmol) were added to the above reaction and degassing was continuedfor another 5 min followed by heating the reaction mixture at 140° C.for 1 h. After completion, the reaction was cooled to room temperatureand passed through a bed of celite. Filtrate was concentrated andtreated with ice-cold water, the precipitated solid was filtered and thecrude was purified by reverse phase prep HPLC. Desired fractions wereconcentrated under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(rac-Cpd. No. 3F) as an off-white solid. The enantiomers were separatedby chiral preparative HPLC [chiralpak IB (4.6×250) mm]. Yield: 1.1 g(85%); Peak 1 (Cpd. No. 3F, 40 mg), [α]_(D) −180.5° (c 0.1, CHCl₃),R_(t)=7.95 min, ee>99%; MS (ESI) m/z 476.35[M+1]⁺; UPLC: 98.31%; ¹H NMR(400 MHz, DMSO-d6) δ 8.21 (d, J=2.0 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H),7.50 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.6 Hz, 2H), 7.03 (t, J=7.2 Hz, 2H),6.97-6.91 (m, 3H), 6.15 (s, 1H), 5.34 (d, J=5.6 Hz, 1H), 4.73 (t, J=5.2Hz, 1H), 4.66 (d, J=13.2 Hz, 1H), 4.34 (dd, J=13.2, 5.2 Hz, 1H), 3.28(s, 3H), 2.78 (s, 3H). Peak 2 (41 mg), [α]_(D) +180° (c 0.1, CHCl₃),R_(t)=15.19 min, ee>98.5%; MS (ESI) m/z 476.35[M+1]⁺; UPLC: 98.76%; ¹HNMR (400 MHz, DMSO-d₆) δ 8.21 (d, J=2.0 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H),7.50 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.6 Hz, 2H), 7.03 (t, J=7.2 Hz, 2H),6.97-6.91 (m, 3H), 6.15 (s, 1H), 5.34 (d, J=5.8 Hz, 1H), 4.73 (t, J=5.4Hz, 1H), 4.66 (d, J=13.2 Hz, 1H), 4.34 (dd, J=13.2, 5.4 Hz, 1H), 3.28(s, 3H), 2.78 (s, 3H).

Example 4(5aR,6S,7R,8R,8aS)-3-cyano-8,8a-dihydroxy-5a-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 4F)

Synthesis of(E)-1-(5-(benzyloxy)-3-hydroxypyridin-2-yl)-3-(4-methoxyphenyl)prop-2-en-1-one(2)

To a solution of 1-(5-(benzyloxy)-3-hydroxypyridin-2-yl)ethan-1-one(42.0 g, 172.8 mmol) and sodium hydroxide (20.97 g, 518.5 mmol) inmethanol (200 mL), 4-methoxybenzaldehyde (31.97 g, 172.8 mmol) was addedand the reaction was heated to reflux for 30 minutes. After completion,reaction mass was cooled and solid was filtered, washed with water anddried under vacuum to afford of(E)-1-(5-(benzyloxy)-3-hydroxypyridin-2-yl)-3-(4-methoxyphenyl)prop-2-en-1-oneas a yellow solid. Yield: 62.3 g, crude; MS (ESI) m/z 362.32[M+1]⁺.

Synthesis of7-(benzyloxy)-3-hydroxy-2-(4-methoxyphenyl)-4H-pyrano[3,2-b]pyridin-4-one(3)

To a solution of(E)-1-(5-(benzyloxy)-3-hydroxypyridin-2-yl)-3-(4-methoxyphenyl)prop-2-en-1-one(2, 54.0 g, 149 mmol) and sodium hydroxide (47.8 g, 1.19 mol) in ethanol(300 mL), hydrogen peroxide (27.6 mL, 747 mmol) was added at roomtemperature. The reaction mass was stirred for 1 h (exotherm wasobserved). After completion, reaction mass was cooled and neutralized topH ˜7 by addition of 6M hydrogen chloride at 0° C. The precipitatedsolid was filtered and dried under vacuum to afford7-(benzyloxy)-3-hydroxy-2-(4-methoxyphenyl)-4H-pyrano[3,2-b]pyridin-4-oneas a pale yellow solid. Yield: 20.5 g, 36%; MS (ESI) m/z 376.11 [M+1]⁺.

Synthesis of rac-methyl(7S,8S,9R)-3-(benzyloxy)-9-hydroxy-6-(4-methoxyphenyl)-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(5)

A solution of7-(benzyloxy)-3-hydroxy-2-(4-methoxyphenyl)-4H-pyrano[3,2-b]pyridin-4-one(18.0 g, 48.0 mmol) and methyl cinnamate (4, 77.8 g, 480.0 mmol) indichloromethane (200 mL) acetonitrile (100 mL) and methanol (100 mL) wasplaced in a UV reactor flask. The reaction mixture was irradiated with400 watts UV light for 15 h. After completion, the solvent was removedunder reduced pressure and the residue was purified over a plug ofsilica gel, eluting the compound with ethyl acetate. The desiredfractions were concentrated under reduced pressure to afford rac-methyl(7S,8S,9R)-3-(benzyloxy)-9-hydroxy-6-(4-methoxyphenyl)-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(5, 15.0 g, crude).

Synthesis of rac-methyl(5aR,6S,7R,8aR)-3-(benzyloxy)-8a-hydroxy-5a-(4-methoxyphenyl)-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(6)

The crude compound rac-methyl(7S,8S,9R)-3-(benzyloxy)-9-hydroxy-6-(4-methoxyphenyl)-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(5, 15.0 g) was suspended in methanol (30 mL) and treated with 25%sodium methoxide in methanol (30 mL) and heated the mixture to 70° C.for 1 h. After completion, the solvent was removed under reducedpressure and crude was treated with ammonium chloride solution andextracted with ethyl acetate. The organic phase was dried over sodiumsulphate and concentrated under reduced pressure to afford rac-methyl(5aR,6S,7R,8aR)-3-(benzyloxy)-8a-hydroxy-5a-(4-methoxyphenyl)-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(6, 12.5 g, crude).

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7)

The above crude compound (6, 12.5 g, 6.0 mmol) was added to a solutionof sodium triacetoxyborohydride (14.8 g, 4.21 mmol) in acetonitrile (130mL) and acetic acid (13.93 mL, 23.27 mmol) and the resulting mixture wasstirred for 6 h at room temperature. After completion, reaction mixturewas partitioned between saturated aqueous sodium bicarbonate solutionand ethyl acetate. The organic layer was separated, dried over sodiumsulphate and concentrated under reduced pressure to get the crude. Thecrude was purified by silica gel column chromatography eluting with50%-70% ethyl acetate in hexanes. The desired fractions wereconcentrated under reduced pressure to afford rac-methyl(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7) as a pale brown solid. Yield: 4.5 g, 35%; MS (ESI) m/z 540.25[M+1]⁺.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3,8,8a-trihydroxy-5a-(4-rnethoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7, 3.0 g, 5.55 mmol) in ethyl acetate (300 mL) at room temperaturepalladium hydroxide (0.195 g, 2.78 mmol, 50% wet) was added. Thereaction was flushed with hydrogen gas twice and stirred under hydrogenpressure at room temperature for 16 h. After completion, the reactionmass was passed through bed of celite and filtrate was concentratedunder reduced pressure to afford rac-methyl(5aR,6S,7R,8R,8aS)-3,8,8a-trihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8) as a brown solid. Yield: 2.8 g, 94%; MS (ESI) m/z 450.17[M+1]⁺.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-3-(((trifluoromethyl)sulfonyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(9)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3,8,8a-trihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8, 2.2 g, 4.8 mmol) and N,N-diisopropylethylamine (0.94 g, 7.3 mmol) indichloromethane (300 mL) was added under nitrogen at −78° C. triflicanhydride (1.79 g, 6.36 mmol) was added slowly. The reaction was stirredfor 30 min at −78° C. and brought to room temperature and stirred for 1h. After completion, the reaction mass was treated with saturated sodiumbicarbonate solution at 0° C. The residue was dissolved indichloromethane (300 mL) separated the organic layer and washed withwater (2×50 mL) then with brine solution (50 mL). The organic layer wasseparated and dried over anhydrous sodium sulfate before concentrationto dryness. The solid was triturated with pentane, filtered and driedunder vacuum to afford rac-methyl(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-3-(((trifluoromethyl)sulfonyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(9) as a brown solid. Yield: 2.5 g, 87.8%; MS (ESI) m/z 582.05[M+1]⁺.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-cyano-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(10)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-3-(((trifluoromethyl)sulfonyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(9, 0.5 g, 0.86 mmol) in dimethylformamide at room temperature, zinccyanide (0.6 g, 5.13 mmol) and zinc (0.067 g, 0.10 mmol) were added anddegassed the reaction with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.023 g, 0.025 mmol),tris(dibenzylideneacetone)dipalladium (0.025 g, 0.034 mmol) were addedto the reaction and degassing was continued with argon for 5 minfollowed by heating at 85° C. for 1 h. After completion, the reactionwas cooled to room temperature and passed through a bed of celite.Filtrate was concentrated and treated with ice-cold water. Theprecipitated solid was filtered and purified by reverse phase prep HPLC.Desired fractions were concentrated to dryness under vacuum to affordrac-methyl(5aR,6S,7R,8R,8aS)-3-cyano-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(10) as a yellow solid. Yield: 150 mg, 38%; MS (ESI) m/z 459.19[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-cyano-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (11)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3-cyano-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(10, 0.42 g, 0.91 mmol) in tetrahydrofuran:water (3:1, 12 mL), lithiumhydroxide (0.066 g, 2.75 mmol) was added and the reaction was stirredfor 6 h at room temperature. After completion, the reaction mass wascooled to 0° C. and acidified with 1M citric acid to pH ˜5. Theprecipitated solid was filtered and dried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-3-cyano-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (11) as an off-white solid. Yield: 0.3 g, 73.7%; MS (ESI) m/z445.19[M+1]⁺.

Synthesis of(5aR,6S,7R,8R,8aS)-3-cyano-8,8a-dihydroxy-5a-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 4F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-cyano-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (11, 0.3 g, 0.67 mmol) in dichloromethane (30 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.388 g, 2.02 mmol),hydroxybenzotriazole (0.27 g, 2.02 mmol) and N,N-diisopropylethylamine(0.52 mg, 4.05 mmol) were added at 0° C. and stirred the mixture for 5min. Dimethylamine.hydrogen chloride (0.274 g, 3.78 mmol) was then addedat same temperature and the mixture was stirred for 12 h at roomtemperature. After completion, reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by silica gel column chromatographyeluting with 70-90% ethyl acetate in hexanes to affordrac-(5aR,6S,7R,8R,8aS)-3-cyano-8,8a-dihydroxy-5a-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(rac-Cpd. No. 4F) as a white solid. The enantiomers were separated bychiral preparative HPLC [chiralpak IB (4.6×250) mm]. Yield: 250 mg,75.9%; Peak 1 (Cpd. No. 4F, 35 mg), [α]_(D) −172.0° (c 0.1, CHCl₃),R_(t)=6.54 min, ee>99%; MS (ESI) m/z 472.33[M+1]⁺; UPLC: 98.98%; ¹H NMR(400 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.00 (s, 1H), 7.07-7.00 (m, 4H), 6.97(d, J=7.0 Hz, 1H), 6.91 (d, J=7.2 Hz, 2H), 6.60 (d, J=8.8 Hz), 6.09 (s,1H), 5.34 (d, J=5.4 Hz, 1H), 4.76 (s, 1H), 4.54 (d, J=12.8 Hz, 1H), 4.25(dd, J=13.5, 5.2 Hz, 1H), 3.59 (s, 3H), 3.26 (s, 3H), 2.77 (s, 3H);Peak-2 (35 mg), [α]_(D) +152.0° (c 0.1, CHCl₃), R_(t)=10.65 min, ee>99%;MS (ESI) m/z 472.34[M+1]⁺; UPLC: 99.58%; ¹H NMR (400 MHz, DMSO-d₆) δ8.60 (d, J=1.4 Hz, 1H), 8.00 (d, J=1.4 Hz, 1H), 7.05-7.01 (m, 4H), 6.97(d, J=7.2 Hz, 1H), 6.91 (d, J=7.4 Hz, 2H), 6.61 (d, J=8.8 Hz, 2H), 6.09(s, 1H), 5.34 (d, J=5.6 Hz, 1H), 4.76 (t, J=5.2 Hz, 1H), 4.54 (d, J=13.2Hz, 1H), 4.25 (dd, J=13.2, 5.2 Hz, 1H), 3.59 (s, 3H), 3.26 (s, 3H), 2.77(s, 3H).

Example 5(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 5F)

Synthesis of 3-(benzyloxy)-5-chloropicolinonitrile (2)

To a solution of 5-chloro-3-nitropicolinonitrile (1, 25.0 g, 273.2 mmol)in tetrahydrofuran (250 mL) under nitrogen sodium hydride (11.0 g, 273.2mmol) was added at room temperature. The suspension was stirred for 30minutes and then benzyl alcohol (29.5 mL, 273.2 mmol) was added andstirring was continued for another 3 h. After completion, the reactionmass was cooled to 0° C. and treated with saturated ammonium chloridesolution. The mixture was diluted with ethyl acetate (200 mL) andorganic layer was separated, washed with water (2×50 mL) and brine (50mL). The organic layer was dried over anhydrous sodium sulfate andsolvent was removed under reduced pressure to get crude. The crude wastreated with pentane (100 mL) to get solid which was filtered and driedunder vacuum to afford 3-(benzyloxy)-5-chloropicolinonitrile (2) asbrownish solid. Yield: 28.0 g, 84%; MS (ESI) m/z 245.09[M+1]⁺.

Synthesis of 1-(3-(benzyloxy)-5-chloropyridin-2-yl)ethan-1-one (3)

To a solution of 3-(benzyloxy)-5-chloropicolinonitrile (2, 28.0 g, 114.0mmol) in dry tetrahydrofuran (250 mL), methyl magnesium bromide (114.0mL, 344.0 mmol) was added dropwise at −30° C. over a period of 30 min.The reaction mass was slowly brought to room temperature and stirred for2 h. After completion, the reaction mixture was treated with 6M hydrogenchloride (pH ˜3) and stirred for another 2 h. The mixture was extractedwith ethyl acetate (200 mL) and layers were separated. The organic layerwas washed with 1M sodium hydroxide solution (50 mL), water (50 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford 1-(3-(benzyloxy)-5-chloropyridin-2-yl)ethan-1-one (3)as a yellow oil. Yield: 19.0 g, 29.9%; MS (ESI) m/z 262.10[M+1]⁺.

Synthesis of 1-(5-chloro-3-hydroxypyridin-2-yl)ethan-1-one (4)

To a solution of 1-(3-(benzyloxy)-5-chloropyridin-2-yl)ethan-1-one (19.0g, 72.7 mmol) in ethylacetate palladium hydroxide (50% wet) (10.0 g,36.3 mmol) was added at room temperature. The reaction was purged withhydrogen gas twice and stirred under hydrogen pressure for 16 h. Aftercompletion, the reaction mass was passed through bed of celite andfiltrate was concentrated under reduced pressure to afford1-(5-chloro-3-hydroxypyridin-2-yl)ethan-1-one as a brown oil. Yield: 8.0g, 64.5%; MS (ESI) m/z 170.03[M−1]⁻.

Synthesis of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-methoxyphenyl)prop-2-en-1-one(5)

To a solution of 1-(5-chloro-3-hydroxypyridin-2-yl)ethan-1-one (4, 8.0g, 46.3 mmol) and sodium hydroxide (5.6 g, 140.0 mmol) in methanol (50mL), mmol) 4-methoxybenzaldehyde (6.9 mL, 56.1 mmol) was added and thereaction was heated to reflux for 30 minutes. After completion, reactionmass was cooled and solid was filtered, washed with water and then driedunder high vacuum to afford of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-methoxyphenyl)prop-2-en-1-one(5) as a yellow solid. Yield: 10.5 g, 77.7%; MS (ESI) m/z 290.02[M+1]⁺.

Synthesis of7-chloro-3-hydroxy-2-(4-methoxyphenyl)-4H-pyrano[3,2-b]pyridin-4-one (6)

To a solution of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-methoxyphenyl)prop-2-en-1-one(5, 10.5 g, 36.3 mmol) and sodium hydroxide (10.0 g, 254.3 mmol) inethanol (100 mL), hydrogen peroxide (10.73 mL, 94.7 mmol) was added atroom temperature. The reaction mass was stirred for 1 h at roomtemperature (exotherm was observed). After completion, reaction mass wascooled and neutralized to pH ˜7 by addition of 6M hydrogen chloride. Theprecipitated solid was filtered and dried under vacuum to afford7-chloro-3-hydroxy-2-(4-methoxyphenyl)-4H-pyrano[3,2-b]pyridin-4-one (6)as a brick red solid. Yield: 6.5 g, 59%; MS (ESI) m/z 304.17[M+1]⁺

Synthesis of rac-methyl(7S,8S,9R)-3-chloro-9-hydroxy-6-(4-methoxyphenyl)-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(8)

A solution of7-chloro-3-hydroxy-2-(4-methoxyphenyl)-4H-pyrano[3,2-b]pyridin-4-one (6,6.5 g, 21.4 mmol) and methyl cinnamate (7, 34.7 g, 214.5 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor. The reaction mixture was irradiated under400 watts UV light for 15 h. After completion, the solvent was removedunder reduced pressure and the residue was purified over a plug ofsilica gel eluting the compound with ethyl acetate. The desiredfractions were concentrated under reduced pressure to afford rac-methyl(7S,8S,9R)-3-chloro-9-hydroxy-6-(4-methoxyphenyl)-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(8, 4.0 g, crude).

Synthesis of rac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-5a-(4-methoxyphenyl)-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(9)

The crude compound rac-methyl(7S,8S,9R)-3-chloro-9-hydroxy-6-(4-methoxyphenyl)-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(8, 4.0 g) was suspended in methanol (30 mL) and treated with 25% sodiummethoxide in methanol (30 mL) and the mixture was heated to 70° C. for 1h. After completion, the solvent was removed under reduced pressure andcrude was treated with ammonium chloride solution and extracted withethyl acetate. The organic phase was separated, dried over sodiumsulphate and concentrated under reduced pressure to afford rac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-5a-(4-methoxyphenyl)-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(9, 2.8 g, crude).

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(10)

The above crude compound (9, 2.8 g, 6.0 mmol) was added to a solution ofsodium triacetoxyborohydride (8.9 g, 42.1 mmol) in acetonitrile (30 mL)and acetic acid (3.6 mL, 60.2 mmol) mixture, the resulting reaction masswas stirred for 4 h at room temperature. After completion, the reactionmixture was partitioned between saturated aqueous sodium bicarbonatesolution (50 mL) and ethyl acetate (100 mL). The organic layer wasseparated, dried over sodium sulphate and concentrated under reducedpressure to get the crude. The crude was purified by silica gel columnchromatography eluting with 50% ethyl acetate in hexanes. The desiredfractions were concentrated to afford rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(10) as a yellow solid. Yield: 0.7 g, 25%; MS (ESI) m/z 468.11[M+1]⁺

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (11)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(10, 0.7 g, 1.48 mmol) in methanol:water (3:1, 12 mL), lithium hydroxide(0.539 g, 22.48 mmol) was added and the reaction was stirred for 6 h atroom temperature. After completion, the reaction mass was cooled to 0°C. and acidified with 1M hydrogen chloride to pH ˜3. The solidprecipitated was filtered and dried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (11) as an off-white solid. Yield: 0.4 g, 58.9%; MS (ESI) m/z452.11[M−1]⁻.

Synthesis of(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 5F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (11, 0.4 g, 0.88 mmol) in dichloromethane (30 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.508 g, 2.6 mmol),hydroxybenzotriazole (0.35 g, 2.6 mmol) and N,N-diisopropylethylamine(0.9 mL, 5.29 mmol) were added at 0° C. and stirred the mixture for 5min. Dimethylamine*hydrogen chloride (0.357 g, 4.41 mmol) was then addedat same temperature and the reaction was stirred for 12 h at roomtemperature. After completion, reaction mass was diluted withdichloromethane (25 mL) and washed with cold water. The organic layerwas separated and dried over sodium sulphate, filtered and concentratedto give crude compound. The crude was purified by silica gel columnchromatography eluting with 70-90% ethyl acetate in hexanes to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-methoxyphenyl)-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(rac-Cpd. No. 5F) as a white solid. The enantiomers were separated usingchiralpak IB (4.6×250) mm column. Yield: 100 mg, 23.5%; Peak 1 (Cpd. No.5F, 30 mg), [α]_(D) −179.0° (c 0.1, CHCl₃), R_(t)=6.87 min, ee>99%; MS(ESI) m/z 481.33[M+1]⁺; UPLC: 99.92%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.18(d, J=2.0 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.04-7.02 (m, 4H), 6.95 (t,J=7.6 Hz, 1H), 6.89 (d, J=7.6 Hz, 2H), 6.61 (d, J=8.8 Hz, 2H), 5.87 (s,1H), 5.22 (d, J=5.6 Hz, 1H), 4.75 (t, J=5.6 Hz, 1H), 4.48 (d, J=13.2 Hz,1H), 4.19 (dd, J=13.2, 6.0 Hz, 1H), 3.60 (s, 3H), 3.25 (s, 3H), 2.76 (s,3H). Peak-2 (50 mg), [α]_(D) +180.0° (c 0.1, CHCl₃), R_(t)=12.16 min,ee>99%; MS (ESI) m/z 481.33[M+1]⁺; UPLC: 99.26%; ¹H NMR (400 MHz,DMSO-d₆) δ 8.18 (d, J=2.0 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.04-7.02 (m,4H), 6.95 (t, J=7.4 Hz, 1H), 6.89 (d, J=7.6 Hz, 2H), 6.61 (d, J=8.8 Hz,2H), 5.88 (s, 1H), 5.22 (d, J=5.5 Hz, 1H), 4.75 (t, J=5.6 Hz, 1H), 4.48(d, J=13.6 Hz, 1H), 4.18 (dd, J=13.6, 5.6 Hz, 1H), 3.60 (s, 3H), 3.25(s, 3H), 2.76 (s, 3H).

Example 6(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-3-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 6F)

Synthesis of 1-(3-hydroxy-5-methoxypyridin-2-yl)ethan-1-one (2)

To a solution of 1-(3,5-dihydroxypyridin-2-yl)ethan-1-one (1, 14.0 g,92.2 mmol) in acetone (50 mL) potassium carbonate (12.7 g, 276.3 mmol)was added under nitrogen atmosphere. Methyl iodide (13.07 g, 92.10 mmol)was added to the above suspension and the reaction was stirred for 6 hat room temperature. After completion, volatiles were removed and thecrude residue was dissolved in ethyl acetate (100 mL) and washed withwater (2×50 mL) and brine solution (50 mL). The organic layer wasseparated and dried over anhydrous sodium sulfate. The crude wastriturated with pentane. The precipitated solid which was filtered anddried under vacuum to afford1-(3-hydroxy-5-methoxypyridin-2-yl)ethan-1-one (2) as a brownish solid.Yield: 8.0 g, 52%.

Synthesis of(E)-3-(4-bromophenyl)-1-(3-hydroxy-5-methoxypyridin-2-yl)prop-2-en-1-one(3)

To a solution of 1-(3-hydroxy-5-methoxypyridin-2-yl)ethan-1-one (2, 8.0g, 47.8 mmol) and sodium hydroxide (5.74 g, 143.6 mmol) in methanol (120mL), 4-bromobenzaldehyde (8.85 g, 47.8 mmol) was added and the mixturewas heated to reflux for 2 h. After completion, the reaction mass wascooled and the solid obtained was filtered, washed with water and driedunder vacuum to afford of(E)-3-(4-bromophenyl)-1-(3-hydroxy-5-methoxypyridin-2-yl)prop-2-en-1-one(3) as a yellow solid. Yield: 14.0 g, 87.7%; MS (ESI) m/z 334.01[M+1]⁺.

Synthesis of2-(4-bromophenyl)-3-hydroxy-7-methoxy-4H-pyrano[3,2-b]pyridin-4-one (4)

To a solution of(E)-3-(4-bromophenyl)-1-(3-hydroxy-5-methoxypyridin-2-yl)prop-2-en-1-one(3, 14.0 g, 36.3 mmol) and sodium hydroxide (11.73 g, 126.1 mmol) inethanol (200 mL) hydrogen peroxide (23.25 mL, 126.1 mmol) was added atroom temperature. The reaction mass was stirred for 1 h (exotherm wasobserved). After completion, reaction mass was cooled and neutralized topH ˜7 by addition of 6M hydrogen chloride. The precipitated solid wasfiltered and dried under vacuum to afford2-(4-bromophenyl)-3-hydroxy-7-methoxy-4H-pyrano[3,2-b]pyridin-4-one (4)as a pale yellow solid. Yield: 12.0 g, 82.53%; MS (ESI) m/z348.05[M+1]⁺.

Synthesis of rac-methyl(7S,8S,9R)-6-(4-bromophenyl)-9-hydroxy-3-methoxy-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(6)

A solution of2-(4-bromophenyl)-3-hydroxy-7-methoxy-4H-pyrano[3,2-b]pyridin-4-one (4,6.0 g, 17.24 mmol) and methyl cinnamate (5, 27.9 g, 172.4 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedunder 400 watts UV light for 15 h. After completion, the solvent wasremoved under reduced pressure and the residue was purified over a plugof silica gel eluting the compound with ethyl acetate. The desiredfractions were concentrated under reduced pressure to afford rac-methyl(7S,8S,9R)-6-(4-bromophenyl)-9-hydroxy-3-methoxy-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(6, 3.5 g, crude).

Synthesis of rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-3-methoxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7)

The crude compound rac-methyl(7S,8S,9R)-6-(4-bromophenyl)-9-hydroxy-3-methoxy-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(6, 3.5 g) was suspended in methanol (20 mL) and treated with 25% sodiummethoxide in methanol (20 mL) and heated the mixture to 70° C. for 1 h.After completion, the solvent was removed under reduced pressure andcrude was treated with ammonium chloride solution and extracted withethyl acetate. The organic phase was separated, dried over sodiumsulphate and concentrated under reduced pressure to rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-3-methoxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7, 3.5 g, crude).

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-3-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8)

The above crude compound (7, 3.5 g, 7.6 mmol) was charged to a solutionof sodium triacetoxyborohydride (9.72 g, 4.58 mmol) in acetonitrile (30mL) and acetic acid (4.57 mL, 60.2 mmol) and the resulting mixture wasstirred for 4 h at room temperature. After completion, reaction mixturewas partitioned between saturated aqueous sodium bicarbonate solutionand ethyl acetate. The organic layer was separated, dried over sodiumsulphate and concentrated under reduced pressure to get the crude. Thecrude was purified by silica gel column chromatography eluting with 50%ethyl acetate in hexanes. The desired fractions were concentrated toafford rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-3-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8) as pale yellow solid. Yield: 0.8 g, 23.5%; MS (ESI) m/z510.03[M−1]⁻.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-3-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(9)

To a mixture of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-3-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8, 0.8 g, 1.56 mmol) in dimethylformamide at room temperature, zinccyanide (1.123 g, 9.59 mmol) and zinc (0.022 g, 0.18 mmol) were addedand degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.041 g, 0.313 mmol) andtris(dibenzylideneacetone)dipalladium (0.078 g, 0.470 mmol) were addedto the above reaction and mixture was degassed with argon for 5 min andthen heated at 140° C. for 2 h. After completion, the reaction wascooled to room temperature and passed through a bed of celite. Thefiltrate was concentrated and treated with ice-cold water. Theprecipitated solid was filtered and the crude product was trituratedwith n-pentane. The solid was filtered and dried under vacuum to affordrac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-3-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(9) as a brown solid. Yield: 0.75 g, crude; MS (ESI) m/z 459.35[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-3-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (10)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-3-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(9, 0.75 g, 1.63 mmol) in methanol:water (3:1, 12 mL), lithium hydroxide(0.411 g, 9.81 mmol) was added and the reaction was stirred for 6 h atroom temperature. After completion, the reaction mass was cooled to 0°C. and acidified with 1M citric acid to pH ˜5. The precipitated solidwas filtered and dried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-3-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (10) as an off-white solid. Yield: 0.6 g, crude; MS (ESI) m/z445.35[M+1]⁺.

Synthesis of(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-3-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 6F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-3-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (10, 0.6 g, 1.35 mmol) in dichloromethane (30 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.77 g, 4.05 mmol),hydroxybenzotriazole (0.54 g, 4.05 mmol) and N,N-diisopropylethylamine(1.04 g, 8.10 mmol) were added at 0° C. and the mixture was stirred for5 min. Dimethylamine hydrochloride (0.55 g, 6.75 mmol) was then addedand the reaction mixture was stirred for 12 h at room temperature. Aftercompletion, reaction mass was diluted with dichloromethane and washedwith cold water. The organic layer was dried over sodium sulphate,filtered and concentrated to give crude. The crude was purified byreverse phase prep HPLC to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-3-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(rac-Cpd. No. 6F) as a white solid. The enantiomers were separated bychiral preparative HPLC [chiralpak IB (4.6×250) mm]. Yield: 110 mg, 17%;Peak 1 (Cpd. No. 6F, 54 mg), [α]_(D) −106° (c 0.1, CHCl₃), R_(t)=6.86min, ee>99%; MS (ESI) m/z 472.37[M+1]⁺; UPLC: 96.33%; 1H NMR (400 MHz,DMSO-d₆) δ 7.9 (d, J=2.0 Hz, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5Hz, 2H), 7.21 (d, J=2.4 Hz, 1H), 7.05 (s, 1H), 7.02 (d, J=7.5 Hz, 1H),6.96 (d, J=7.2 Hz, 1H), 6.90 (d, J=7.4 Hz, 2H), 5.88 (s, 1H), 5.16 (brs,1H), 4.77 (brs, 1H), 4.54 (d, J=13.2 Hz, 1H), 4.25 (dd, J=13.2, 5.8 Hz,1H), 3.86 (s, 3H), 3.26 (s, 3H), 2.77 (s, 3H). Peak 2 (45 mg), [α]_(D)+147.1° (c 0.1, CHCl₃), R_(t)=12.85 min, ee>99%; MS (ESI) m/z472.37[M+1]⁺; UPLC: 99.95%; 1H NMR (400 MHz, DMSO-d6) δ 7.9 (d, J=2.4Hz, 1H), 7.52 (d, J=8.6 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.22 (d, J=2.2Hz, 1H), 7.05 (s, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H),6.91 (d, J=7.4 Hz, 2H), 5.88 (s, 1H), 5.17 (brs, 1H), 4.78 (d, J=5.6 Hz,1H), 4.55 (d, J=13.2 Hz, 1H), 4.27 (dd, J=13.2, 5.6 Hz 1H), 3.86 (s,3H), 3.26 (s, 3H), 2.77 (s, 3H).

Example 7(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(p-tolyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 7F)

Synthesis of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(p-tolyl)prop-2-en-1-one (3)

To a solution of 1-(5-chloro-3-hydroxypyridin-2-yl)ethan-1-one (1, 6.0g, 34.9 mmol) in methanol (30 mL), sodium hydroxide (4.19 g, 104.9 mmol)and 4-methylbenzaldehyde (2, 4.19 g, 34.9 mmol) were added. The reactionmixture was heated at 85° C. for 2 h. After completion, reaction masswas cooled and obtained solid was filtered, washed with water and driedunder vacuum to afford of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(p-tolyl)prop-2-en-1-one (3) asyellow solid. Yield: 5.0 g, 52.08%; MS (ESI) m/z 274.13[M+1]⁺.

Synthesis of7-chloro-3-hydroxy-2-(p-tolyl)-4H-pyrano[3,2-b]pyridin-4-one (4)

To a solution of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(p-tolyl)prop-2-en-1-one (3,5.0 g, 18.3 mmol) in ethanol/dichloromethane (1:1, 20 mL), sodiumhydroxide (6.45 g, 161.15 mmol) was added followed by addition of 30%hydrogen peroxide (4.8 mL, 161.15 mmol) at room temperature. Thereaction mass was stirred for 1 h (exotherm was observed). Aftercompletion, reaction mass was cooled and neutralized by addition of 6 Mhydrogen chloride. The precipitated solid was filtered and dried undervacuum to afford7-chloro-3-hydroxy-2-(p-tolyl)-4H-pyrano[3,2-b]pyridin-4-one (4) asbrown solid. Yield: 1.66 g, 25%; MS (ESI) m/z 288.14[M+1]⁺.

Synthesis of rac-methyl3-chloro-7a-hydroxy-8-oxo-6-phenyl-5a-(p-tolyl)-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carboxylate(6/6a)

A solution of7-chloro-3-hydroxy-2-(p-tolyl)-4H-pyrano[3,2-b]pyridin-4-one (4, 1.3 g,4.5 mmol) and methyl cinnamate (5, 6.99 g, 45.1 mmol) in dichloromethane(200 mL), acetonitrile (100 mL) and methanol (100 mL) was placed in a UVreactor flask. The reaction mixture was irradiated for 15 h under 400watts UV light. After completion, the solvent was removed under reducedpressure and the residue was purified by Combi-flash (12 g, RediSepcolumn) using ethyl acetate as eluent. The desired fractions wereconcentrated under reduced pressure to afford rac-methyl3-chloro-7a-hydroxy-8-oxo-6-phenyl-5a-(p-tolyl)-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carboxylate(6/6a). Yield: 1.1 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a-(p-tolyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7)

The crude rac-methyl3-chloro-7a-hydroxy-8-oxo-6-phenyl-5a-(p-tolyl)-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carboxylate(6, 1.1 g) was suspended in methanol (10 mL) and sodium methoxide (25%in methanol, 10 mL) was added. The reaction mixture was heated to 90° C.for 1 h. After completion, the solvent was removed under reducedpressure and the reaction was quenched with ammonium chloride solutionand extracted with ethyl acetate. The organic phase was separated, driedover anhydrous sodium sulphate and concentrated under reduced pressureto afford rac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a-(p-tolyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7). Yield: 0.9 g; crude.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(p-tolyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8)

To a solution of rac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a-(p-tolyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7, 0.9 g) in acetonitrile (10 mL), sodium triacetoxyborohydride (2.54g, 11.9 mmol) and acetic acid (1.1 mL, 20.0 mmol) were added. Theresulting mixture was stirred for 16 h at room temperature. Aftercompletion, reaction mixture was partitioned between saturated aqueoussodium bicarbonate solution and ethyl acetate. The organic layer wasseparated, dried over anhydrous sodium sulphate and concentrated underreduced pressure to get the crude. The crude was purified by Combi-flash(4 g, RediSep column) using 70% ethyl acetate in hexanes as eluent. Thedesired fractions were concentrated to afford rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(p-tolyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8) as light yellow solid. Yield: 0.25 g, 27%; MS (ESI) m/z452.33[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(p-tolyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(p-tolyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8, 0.25 g, 0.55 mmol) in tetrahydrofuran and water (3:1, 4.0 mL),lithium hydroxide (0.26 g, 11.0 mmol) was added and the reaction wasstirred for 6 h at room temperature. After completion, the reaction masswas cooled to 0° C. and acidified with 1M hydrogen chloride to pH ˜3.The precipitated solid was filtered and washed with water and driedunder vacuum to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(p-tolyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9) as yellow solid. Yield: 0.13 g, 54.0%; MS (ESI) m/z438.32[M+1]⁺.

Synthesis of(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(p-tolyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 7F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(p-tolyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9, 0.13 g, 29.7 mmol) in dichloromethane (5.0 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.046 g,0.50 mmol), 1-hydroxybenzotriazole (0.067 g, 0.49 mmol) andN,N-diisopropylethylamine (0.15 mL, 0.49 mmol) were added at 0° C. andstirred the mixture for 5 min. Dimethylamine hydrochloride (0.032 g,0.34 mmol) was then added at same temperature and the mixture wasstirred at room temperature for 16 h. After completion, reaction masswas diluted with dichloromethane and washed with cold water. The organiclayer was separated and dried over sodium sulphate, filtered andconcentrated to give crude. The crude was purified by Combi-flash (4 g,RediSep column) using 70% ethyl acetate in hexanes as eluent. Thedesired fractions were concentrated under reduced pressure to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(p-tolyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(rac-Cpd. No. 7F) as white solid. Yield: 0.07 mg, 50%, MS (ESI) m/z465.32[M+1]⁺. The enantiomers were separated by chiral preparative HPLC[chiralpak IB (4.6×250) mm]. Peak 1 (13 mg); [α]_(D) +212.0° (c 0.1,CHCl₃); R_(t)=10.18 min, ee>95%; MS (ESI) m/z 465.32[M+1]⁺; UPLC 97.1%;¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (d, J=2.0 Hz, 1H), 7.69 (d, J=2.0 Hz,1H), 7.11-6.94 (m, 5H), 6.90 (d, J=8.2 Hz, 2H), 6.86 (d, J=8.2 Hz, 2H),5.88 (s, 1H), 5.23 (t, J=5.5, 1H), 4.77 (t, J=5.6 Hz, 1H), 4.51 (d,J=13.2 Hz, 1H), 4.23-4.18 (dd, J=13.2, 5.6 Hz, 1H), 3.25 (s, 3H), 2.76(s, 3H), 2.11 (s, 3H). Peak-2 (Cpd. No. 7F, 9 mg); [α]_(D) −191.1° (c0.1, CHCl₃); R_(t)=22.4 min, ee>99%; MS (ESI) m/z 465.32[M+1]⁺; UPLC99.8%; 1H NMR (400 MHz, DMSO-d₆) δ 8.18 (d, J=2.0 Hz, 1H), 7.69 (d,J=2.0 Hz, 1H), 7.03-6.94 (m, 5H), 6.90 (d, J=8.2 Hz, 2H), 6.86 (d, J=8.2Hz, 2H), 5.88 (s, 1H), 5.23 (d, J=5.6, 1H), 4.77 (t, J=5.6 Hz, 1H), 4.50(d, J=13.2 Hz, 1H), 4.23-4.18 (dd, J=13.2, 5.6 Hz, 1H), 3.25 (s, 3H),2.76 (s, 3H), 2.11 (s, 3H).

Example 8(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 8F)

Synthesis of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(3)

To a solution of 1-(5-chloro-3-hydroxypyridin-2-yl)ethan-1-one (1, 6.0g, 35.08 mmol) in methanol (20 mL), sodium hydroxide (4.2 g, 105.24mmol) and 4-(trifluoromethyl)benzaldehyde (2, 6.1 g, 35.8 mmol) wereadded. The reaction mixture was heated at 90° C. for 1 h. Aftercompletion, reaction mass was cooled and precipitated solid wasfiltered, washed with water and dried under vacuum to afford of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(3) as yellow solid. Yield: 6.0 g, 55%; MS (ESI) m/z 328.26[M+1]⁺.

Synthesis of7-chloro-3-hydroxy-2-(4-(trifluoromethyl)phenyl)-4H-pyrano[3,2-b]pyridin-4-one(4)

To a solution of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(3, 6.0 g, 18.3 mmol) in ethanol/dichloromethane (1:1, 200 mL), 10%sodium hydroxide (50.1 mL, 128.4 mmol) was added followed by addition of30% hydrogen peroxide (12.5 mL, 128.4 mmol) at room temperature. Thereaction mass was stirred for 30 min (exotherm was observed). Aftercompletion, reaction mass was cooled and neutralized with 6 M hydrogenchloride to pH ˜7, then dichloromethane was distilled off andprecipitated solid was filtered and washed with ethanol and n-pentane.Solid dried under vacuum to afford7-chloro-3-hydroxy-2-(4-(trifluoromethyl)phenyl)-4H-pyrano[3,2-b]pyridin-4-one(4) as light orange solid. Yield: 3.5 g, 56%; MS (ESI) m/z 342.06[M+1]⁺.

Synthesis of rac-methyl(6R,7S,8S,9R)-3-chloro-9-hydroxy-10-oxo-7-phenyl-6-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate (6/6a)

A solution of7-chloro-3-hydroxy-2-(4-(trifluoromethyl)phenyl)-4H-pyrano[3,2-b]pyridin-4-one(4, 3.0 g, 8.79 mmol) and methyl cinnamate (5, 14.2 g, 87.9 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedfor 24 h under 400 watts UV light. After completion, the solvent wasremoved under reduced pressure and the residue was purified byCombi-flash (24 g RediSep column) using ethyl acetate as eluent. Thedesired fractions were concentrated under reduced pressure to affordrac-methyl(6R,7S,8S,9R)-3-chloro-9-hydroxy-10-oxo-7-phenyl-6-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(6/6a) as brown sticky solid. Yield: 3.0 g, crude; MS (ESI) m/z504.39[M+1]⁺.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7)

The crude rac-methyl(6R,7S,8S,9R)-3-chloro-9-hydroxy-10-oxo-7-phenyl-6-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(6/6a, 3.0 g, 5.96 mmol) was suspended in methanol (30 mL) and treatedwith sodium methoxide (25% in methanol, 30 mL) and heated the mixture at90° C. for 3 h. After completion, the solvent was removed under reducedpressure. The crude was diluted with ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover anhydrous sodium sulphate and concentrated under reduced pressureto afford rac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7) as brown sticky solid. Yield: 2.5 g, crude; MS (ESI) m/z504.10[M+1]⁺.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8)

To a solution of rac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7, 2.5 g, 4.97) in acetonitrile (250 mL), sodium triacetoxyborohydride(6.0 g, 29.82 mmol) and acetic acid (3.0 mL, 49.7 mmol) were added at 0°C. The resulting mixture was stirred for 10 h at room temperature. Aftercompletion, reaction mixture was partitioned between saturated aqueoussodium bicarbonate solution and ethyl acetate. The organic layer wasseparated, dried over anhydrous sodium sulphate and concentrated underreduced pressure to get the crude. The crude was purified by Combi-flash(12 g RediSep column) using 70% ethyl acetate in hexanes as eluent. Thedesired fractions were concentrated to afford rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8) as off white solid. Yield: 1.1 g, 44%; MS (ESI) m/z 506.8[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8, 1.1 g, 2.1 mmol) in methanol and water (3:1, 13 mL), lithiumhydroxide (2.19 g, 52.2 mmol) was added and the reaction was stirred for3 h at room temperature. After completion, the reaction mass was cooledto 0° C. and acidified with 6 M hydrogen chloride to pH ˜6. Theprecipitated solid was filtered and dried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9) as off white solid. Yield: 900 mg, 85%; MS (ESI) m/z492.5[M+1]⁺

Synthesis of(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 8F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9, 0.90 g, 1.83 mmol) in dichloromethane (50 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.0 g, 5.4mmol), 1-hydroxybenzotriazole (0.74 g, 5.4 mmol) andN,N-diisopropylethylamine (1.9 mL, 10.9 mmol) were added at 0° C. andstirred the mixture for 5 min. Dimethylamine hydrochloride (0.74 g, 9.1mmol) was then added at same temperature and the mixture was stirred for20 h at room temperature After completion, reaction mass was dilutedwith dichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by Combi-flash (4 gRediSep column) using 5% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 8F) as off white solid. Yield: 0.5 g, 53%; the enantiomerswere separated by chiral preparative HPLC [chiralpak ID (4.6×250) mm].Peak 1 (50 mg); [α]_(D) +212.0° (c 0.1, CHCl₃); R_(t)=6.26 min, ee>99%;MS (ESI) m/z 519.30[M+1]+; UPLC 97%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.21(d, J=2.0 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.35 (dd, J=13.6 Hz, 8.9 Hz,4H), 7.04-7.00 (m, 2H), 6.96-6.91 (m, 3H), 6.13 (s, 1H), 5.34 (d, J=5.6Hz, 1H), 4.77 (t, J=5.4 Hz, 1H), 4.64 (d, J=13.2 Hz, 1H), 4.34 (dd,J=13.2, 5.2 Hz, 1H), 3.28 (s, 3H), 2.78 (s, 3H). Peak-2 (Cpd. No. 8F, 50mg); [α]_(D) −194.5° (c 0.1, CHCl₃); R_(t)=12.49 min, ee>99%; MS (ESI)m/z 519.31[M+1]+; UPLC 99%; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.21 (d, J=2.0Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.35 (dd, J=13.6 Hz, 8.9 Hz, 4H),7.04-7.00 (m, 2H), 6.96-6.91 (m, 3H), 6.13 (s, 1H), 5.34 (d, J=5.6 Hz,1H), 4.77 (t, J=5.4 Hz, 1H), 4.64 (d, J=13.2 Hz, 1H), 4.34 (dd, J=13.2,5.2 Hz, 1H), 3.28 (s, 3H), 2.78 (s, 3H).

Example 9(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 9F)

Synthesis of 1-(3-hydroxypyridin-2-yl)ethan-1-one (2)

To a solution of 3-hydroxypicolinonitrile (1, 7.0 g, 58.2 mmol) in drytetrahydrofuran (100 mL), 3 M methyl magnesium bromide in diethyl ether(58.0 mL, 174.84 mmol) was added drop wise over a period of 30 min at 0°C. The reaction mass was slowly brought to room temperature and stirredfor 2 h. After completion, the reaction mass was treated with 6 Mhydrogen chloride upto pH˜3 and stirred for 2 h. Then extracted thecrude with ethyl acetate. The organic layer was washed with aqueoussodium hydroxide, dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to afford1-(3-hydroxypyridin-2-yl)ethan-1-one (2) as yellow solid. Yield: 6.5 g,81.3%, crude.

Synthesis of(E)-3-(4-bromophenyl)-1-(3-hydroxypyridin-2-yl)prop-2-en-1-one (4)

To a solution of 1-(3-hydroxypyridin-2-yl)ethan-1-one (2, 6.5 g, 47.4mmol) in methanol (50 mL), sodium hydroxide (5.7 g, 142.1 mmol) wasadded followed by addition of 4-bromobenzaldehyde (3, 10.5 g, 56.8 mmol)and the reaction mixture was heated at 90° C. for 1 h. After completion,reaction mass was cooled and obtained solid was filtered, washed withwater and dried under vacuum to afford of(E)-3-(4-bromophenyl)-1-(3-hydroxypyridin-2-yl)prop-2-en-1-one (4) aslight yellow solid. Yield: 10.2 g, 70.7%; MS (ESI) rm/z 304.09[M+1]⁺.

Synthesis of 2-(4-bromophenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one(5)

To a solution of(E)-3-(4-bromophenyl)-1-(3-hydroxypyridin-2-yl)prop-2-en-1-one (4, 10.0g, 46.03 mmol) in dichloromethane and ethanol (1:1, 50 mL), 10% sodiumhydroxide (92.0 mL, 322.2 mmol) was added followed by addition of 30%hydrogen peroxide (25 mL, 322.2 mmol) at room temperature. The reactionmass was stirred for 1 h (exotherm was observed). After completion,reaction mass was cooled and neutralized with 6 M hydrogen chloride topH ˜7. The solvents were concentrated to half volume, the precipitatedsolid was filtered and dried under vacuum to afford2-(4-bromophenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one (5) as yellowsolid. Yield: 3.7 g, 26.4%; MS (ESI) m/z 318.19[M+1]⁺.

Synthesis of rac-methyl 5a-(4-bromophenyl)-7a-hydroxy-8-oxo-6-phenyl-5a,6, 7a, 8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carboxylate (7/8)

A solution of 2-(4-bromophenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one(5, 3.7 g, 11.6 mmol) and methyl cinnamate (6, 13.2 g, 81.4 mmol) indichloromethane (200 mL), acetonitrile (50 mL) and methanol (50 mL) wasplaced in a UV reactor flask. The reaction mixture was irradiated for 24h under 400 watts UV light. After completion, the solvent was removedunder reduced pressure. The crude was purified by Combi-flash (24 g,RediSep column) using 80% ethyl acetate in hexanes as eluent. Thedesired fractions were concentrated under reduced pressure to affordrac-methyl5a-(4-bromophenyl)-7a-hydroxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carboxylate(7/8) as yellow solid. Yield: 3.5 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(9)

The crude rac-methyl5a-(4-bromophenyl)-7a-hydroxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carboxylate(7/8, 3.5 g) was suspended in methanol (20 mL) and treated with sodiummethoxide (25% in methanol, 13.1 mL) and heated the mixture to 90° C.for 3 h. After completion, the solvent was removed under reducedpressure, diluted the mixture with ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and concentrated under reduced pressure to affordrac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(9) as yellow solid. Yield: 3.0 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(10)

To a solution of sodium triacetoxyborohydride (5.6 g, 31.2 mmol),rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(9, 2.5 g) in acetonitrile (30 mL), acetic acid (3.13 g, 52.05 mmol) wasadded. The resulting mixture was stirred for 4 h at room temperature.After completion, reaction mixture was partitioned between saturatedaqueous sodium bicarbonate solution and ethyl acetate. The organic layerwas separated, dried over sodium sulphate and concentrated under reducedpressure to get the crude. The crude was purified by Combi-flash (12 g,RediSep column) using 50%-70% ethyl acetate in hexanes as eluent. Thedesired fractions were concentrated under reduced pressure to affordrac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(10) as yellow solid. Yield: 0.9 g, 37%; MS (ESI) m/z 482.19[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (11)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(10, 0.9 g, 1.87 mmol) in tetrahydrofuran and water (3:1, 30 mL),lithium hydroxide (0.80 g, 37.3 mmol) was added and the reaction wasstirred for 16 h at room temperature. After completion, the reactionmass was cooled to 0° C. and acidified with 6M hydrogen chloride to pH˜3. The precipitated solid was filtered and dried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (11) as light yellow solid. Yield: 0.75 g, 86%; MS (ESI) m/z466.15[M−1]⁻.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(12)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (11, 0.75 g, 1.60 mmol) in dichloromethane (15 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.614 g,3.2 mmol), 1-hydroxybenzotriazole (0.43 g, 3.20 mmol) andN,N-diisopropylethylamine (0.85 mL, 4.8 mmol) were added at 0° C. andstirred the mixture for 5 min. Dimethylamine hydrochloride (0.21 g, 3.20mmol) was then added at same temperature and the mixture was stirred for16 h at room temperature. After completion, reaction mass was dilutedwith dichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by Combi-flash (12 g, RediSep column)using 70% ethyl acetate in hexanes as eluent. The desired fractions wereconcentrated to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(12) as light yellow solid. Yield: 0.450 g, 56%; MS (ESI) m/z495.21[M+1]⁺.

Synthesis of(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 9F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(12, 0.25 g, 0.504 mmol) in N,N-dimethylformamide (20.0 mL), zinccyanide (0.335 g, 3.24 mmol) and zinc (0.001 g, 0.014 mmol) were addedat room temperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.007 g, 0.010 mmol),tris(dibenzylideneacetone)dipalladium (0.014 g, 0.015 mmol) were addedto the reaction and degassing was continued for another 5 min. Thereaction mixture was heated at 140° C. for 5 h. After completion, thereaction was cooled to room temperature and passed through celite bed.The filtrate was diluted with ethyl acetate and washed with water. Theorganic layer was separated, dried over sodium sulphate and concentratedunder reduced pressure to get the crude. The crude was purified byCombi-flash (4 g, RediSep column) using 80%-100% ethyl acetate inhexanes as eluent. The desired fractions were concentrated under reducedpressure to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(rac-Cpd. No. 9F) as white solid. The enantiomers were separated bychiral preparative HPLC [chiralpak IA (4.6×250) mm]. Yield: 210 mg, 93%;Peak 1 (25 mg), [α]_(D) +136° (c 0.23, CHCl₃), R_(t)=7.70 min, ee>99%;MS (ESI) m/z 442.40[M+1]⁺; UPLC: 98.86%; ¹H NMR (400 MHz, DMSO-d₆) δ8.18 (d, J=1.6 Hz, 1H), 7.50 (d, J=8.4 Hz, 3H), 7.36-7.29 (m, 3H),7.05-7.01 (m, 2H), 6.97-6.91 (m, 3H), 6.05 (s, 1H), 5.25 (d, J=5.6 Hz,1H), 4.79 (t, J=5.2 Hz, 1H), 4.58 (d, J=13.2 Hz, 1H), 4.30 (dd, J=13.2,5.2 Hz, 1H), 3.28 (s, 3H), 2.77 (s, 3H); Peak-2 (Cpd. No. 9F, 38 mg),[α]_(D) −166° (c 0.24, CHCl₃), R_(t)=13.92 min, ee>95%; MS (ESI) m/z442.4[M+1]⁺; UPLC: 98.93%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (d, J=1.6Hz, 1H), 7.50 (d, J=8.4 Hz, 3H), 7.36-7.29 (m, 3H), 7.05-7.01 (m, 2H),6.97-6.91 (m, 3H), 6.05 (s, 1H), 5.25 (d, J=5.6 Hz, 1H), 4.79 (t, J=5.2Hz, 1H), 4.58 (d, J=13.2 Hz, 1H), 4.30 (dd, J=13.2, 5.2 Hz, 1H), 3.28(s, 3H), 2.77 (s, 3H).

Example 10(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-fluorophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 10F)

Synthesis of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-fluorophenyl)prop-2-en-1-one(2)

To a solution of 1-(5-chloro-3-hydroxypyridin-2-yl)ethan-1-one (1, 5.0g, 29.23 mmol) in methanol (25 mL), sodium hydroxide (3.5 g, 87.71 mmol)was added followed by addition of 4-fluorobenzaldehyde (4.35 g, 35.08mmol) and the reaction mixture was heated at 80° C. for 1 h. Aftercompletion, reaction mass was cooled and precipitated solid wasfiltered, washed with water and dried under vacuum to afford of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-fluorophenyl)prop-2-en-1-one(2) as pale yellow solid. Yield: 4.2 g, 51.8%; MS (ESI) m/z276.16[M−1]⁻.

Synthesis of7-chloro-2-(4-fluorophenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one (3)

To a solution of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-fluorophenyl)prop-2-en-1-one(2, 3.0 g, 10.81 mmol) in ethanol/dichloromethane (1:1, 100 mL), 10%sodium hydroxide solution (30.0 mL, 75.81 mmol) was added followed byaddition of hydrogen peroxide (30% solution, 6.7 mL, 54.1 mmol) at roomtemperature. The reaction mass was stirred for 1 h (exotherm wasobserved). After completion, reaction mass was poured on ice cold waterand neutralized by addition of 6 M hydrogen chloride and extracted withdichloromethane (100 mL). The organic layer was separated, dried oversodium sulphate, filtered and concentrated under reduced pressure to getcrude. The crude was triturated with diethylether and n-pentane toafford7-(chloro)-2-(4-fluoroophenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one(3) as yellow solid. Yield: 2.5 g, 79.6%; MS (ESI) m/z 290.07[M−1]⁻.

Synthesis of rac-methyl3-chloro-5a-(4-fluorophenyl)-7a-hydroxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carboxylate(5/5a)

A solution of7-(chloro)-2-(4-fluoroophenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one(3, 2.5 g, 8.59 mmol) and methyl cinnamate (4, 13.9 g, 85.7 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedunder 400 watts UV light for 16 h. After completion, the solvent wasremoved under reduced pressure. The residue was purified by Combi-flash(24 g, RediSep column) using ethyl acetate as eluent. The desiredfractions were concentrated under reduced pressure to afford rac-methyl3-chloro-5a-(4-fluorophenyl)-7a-hydroxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carboxylate(5/5a). Yield: 2.5 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-3-chloro-5a-(4-fluorophenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(6)

The crude rac-methyl3-(chloro)-5a-(4-fluoroophenyl)-7a-hydroxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carboxylate(5, 1.3 g) was suspended in methanol (15 mL) and treated with sodiummethoxide (25% in methanol, 15 mL) and heated the mixture at 80° C. for1 h. After completion, the solvent was removed under reduced pressureand the reaction was treated with ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and concentrated under reduced pressure to affordrac-methyl(5aR,6S,7R,8aR)-3-chloro-5a-(4-fluorophenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(6). Yield: 1.4 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-fluorophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7)

To a solution of sodium triacetoxyborohydride (1.8 g, 2.86 mmol),rac-methyl(5aR,6S,7R,8aR)-3-(chloro)-5a-(4-fluorophenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(6, 1.3 g) in acetonitrile (50 mL), acetic acid (1.7 mL, 28.69 mmol) wasadded. The resulting mixture was stirred for 4 h at room temperature.After completion, reaction mixture was partitioned between saturatedaqueous sodium bicarbonate solution and ethyl acetate. The organic layerwas separated, dried over sodium sulphate and concentrated under reducedpressure to get the crude. The crude was purified by Combi-flash (4 g,RediSep column) using 50% ethyl acetate in hexanes as eluent. Thedesired fractions were concentrated under reduced pressure to affordrac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-fluorophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7) as light yellow solid. Yield: 0.32 g, 24.6%; MS (ESI) m/z456.17[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-fluorophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (8)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-fluoroophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7, 0.30 g, 0.65 mmol) in methanol and water (3:1, 12 mL), lithiumhydroxide (0.158 g, 6.59 mmol) was added and the reaction was stirredfor 6 h at room temperature. After completion, the reaction mass wascooled to 0° C. and acidified with 6 M hydrogen chloride to pH ˜3. Theprecipitated solid was filtered and dried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-fluorophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (8) as yellow solid. Yield: 0.25 g, 86.2%; MS (ESI) m/z442.20[M+1]⁺.

Synthesis of(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-fluorophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 10F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-fluorophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (8, 0.25 g, 0.566 mmol) in dichloromethane (10 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.32 g,1.70 mmol), 1-hydroxybenzotriazole (0.23 g, 1.70 mmol) andN,N-diisopropylethylamine (0.6 mL, 3.4 mmol) were added at 0° C. andstirred the mixture for 5 min. Dimethylamine hydrochloride (0.23 g, 2.83mmol) was then added at same temperature and the mixture was stirred for16 h at 40° C. After completion, reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by Combi-flash (12 g, RediSep column)using 5% methanol in dichloromethane as eluent. The desired fractionswere concentrated under reduced pressure to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-fluorophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(rac-Cpd. No. 10F). The enantiomers were separated by chiral preparativeHPLC [chiralpak ID (4.6×250) mm]. Yield: 100 mg, 38%; Peak 1 (26 mg);[α]_(D) +182.2° (c 0.3, CHCl₃); R_(t)=5.88 min, ee>99%; MS (ESI) m/z469.34[M+1]⁺; UPLC: 99.07%; 1H NMR (400 MHz, DMSO-d₆) δ 8.20 (d, J=1.9Hz, 1H), 7.70 (d, J=1.9 Hz, 1H), 7.16-7.13 (m, 2H), 7.02 (t, J=7.2 Hz,2H), 6.97-6.93 (m, 1H), 6.90-6.87 (m, 4H), 6.01 (s, 1H), 5.28 (d, J=5.6Hz, 1H), 4.75 (t, J=5.5 Hz, 1H), 4.53 (d, J=13.3 Hz, 1H), 4.22 (dd,J=13.2, 5.4 Hz, 1H), 3.26 (s, 3H), 2.77 (s, 3H). Peak-2 (Cpd. No. 10F,34 mg); [α]_(D) −201.4° (c 0.29, CHCl₃); R_(t)=10.86 min, ee>99%; MS(ESI) rmz 469.34 [M+1]⁺; UPLC: 99.78%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.20(d, J=1.9 Hz, 1H), 7.70 (d, J=1.9 Hz, 1H), 7.16-7.13 (m, 2H), 7.03 (t,J=7.2 Hz, 2H), 6.97-6.82 (m, 4H), 6.01 (s, 1H), 5.28 (d, J=5.6 Hz, 1H),4.75 (t, J=5.5 Hz, 1H), 4.53 (d, J=13.2 Hz, 1H), 4.22 (dd, J=13.3, 5.4Hz, 1H), 3.26 (s, 3H), 2.77 (s, 3H).

Example 11(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 11F)

Synthesis of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-chlorophenyl)prop-2-en-1-one(3)

To a solution of 1-(5-chloro-3-hydroxypyridin-2-yl)ethan-1-one (1, 4.0g, 23.4 mmol) in methanol (20 mL), sodium hydroxide (2.8 g, 70.2 mmol)was added followed by addition of 4-chlorobenzaldehyde (2, 3.3 g, 23.4mmol). The reaction was heated to reflux for 10 min. After completion,the reaction mass was cooled to room temperature and diluted with water(20 mL). The precipitated solid was filtered, washed with water,n-pentane and dried under vacuum to afford(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-chlorophenyl)prop-2-en-1-one(3) as yellow solid. Yield: 6.1 g, 89.0%; MS (ESI) m/z 292.15[M−1]⁻.

Synthesis of7-chloro-2-(4-chlorophenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one (4)

To a solution of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-chlorophenyl)prop-2-en-1-one(3, 7.0 g, 23.9 mmol) in ethanol (400 mL) and dichloromethane (66 mL) at0° C., 10% aqueous sodium hydroxide (6.7 g, 167.2 mmol) was addedfollowed by the addition of 30% aqueous hydrogen peroxide (37.5 mL,334.4 mmol). The reaction mass was stirred for 30 min at roomtemperature (exotherm was observed). After completion, the reaction masswas cooled and neutralized to pH ˜7 by the addition of 6 M hydrogenchloride. The mixture was extracted with ethyl acetate (100 mL) and theorganic layer was washed with water and brine, dried over anhydroussodium sulfate, filtered and concentrated. The solid obtained wastriturated with ethanol, filtered and dried under vacuum to afford7-chloro-2-(4-chlorophenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one (4)as light yellow solid. Yield: 2.81 g, 38.2%; MS (ESI) m/z 308.04[M+1]⁺.

Synthesis of rac-methyl3-chloro-5a-(4-chlorophenyl)-7a-hydroxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carboxylate(6)

A solution of7-chloro-2-(4-chlorophenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one (4,2.8 g, 9.12 mmol) and methyl cinnamate (5, 14.7 g, 91.2 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedfor 8 h under 400 watts UV light. After completion, solvent was removedunder reduced pressure and the residue was purified over a plug ofsilica gel eluting the compound with ethyl acetate. The desiredfractions were concentrated under reduced pressure to afford rac-methyl3-chloro-5a-(4-chlorophenyl)-7a-hydroxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carboxylate(6) as brown solid. Yield: 3.1 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-3-chloro-5a-(4-chlorophenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7)

The crude rac-methyl3-chloro-5a-(4-chlorophenyl)-7a-hydroxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carboxylate(6, 3.1 g, 6.6 mmol) was suspended in methanol (30 mL) and treated with25% sodium methoxide in methanol (20 mL). The reaction was heated at 80°C. for 2 h. After completion, the solvent was removed under reducedpressure and crude was diluted with aqueous ammonium chloride solutionand extracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and concentrated under reduced pressure to affordrac-methyl(5aR,6S,7R,8aR)-3-chloro-5a-(4-chlorophenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7). Yield: 2.35 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8)

To a solution of sodium triacetoxyborohydride (6.23 g, 29.4 mmol),rac-methyl(5aR,6S,7R,8aR)-3-chloro-5a-(4-chlorophenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7, 2.3 g, 4.9 mmol) in acetonitrile (60 mL), acetic acid (3.0 g, 49.0mmol) was added. The resulting mixture was stirred for 18 h at roomtemperature. After completion, the reaction mixture was partitionedbetween saturated aqueous sodium bicarbonate solution and ethyl acetate.The organic layer was separated and dried over sodium sulphate, filteredand concentrated to give crude. The crude was purified by silica gelcolumn chromatography using 60% ethyl acetate in hexanes as eluent. Thedesired fractions were concentrated under reduced pressure to affordrac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8) as white solid. Yield: 1.1 g, 25.6%; MS (ESI) m/z 472.15[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8, 1.0 g, 2.12 mmol) in methanol, tetrahydrofuran and water (3:2:1, 18mL), lithium hydroxide (0.89 g, 21.2 mmol) was added and the reactionwas stirred for 3 h at room temperature. After completion, the reactionmass was cooled to 0° C. and acidified with 1 M hydrochloric acid to pH˜2-3. The precipitate was filtered and dried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9) as white solid. Yield: 0.55 g, 56.7%; MS (ESI) m/z458.14[M+1]⁺.

Synthesis of(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 11F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9, 0.3 g, 0.65 mmol) in dichloromethane (8 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.30 g, 1.95 mmol),hydroxybenzotriazole (0.29 g, 1.95 mmol) and N,N-diisopropylethylamine(0.51 g, 3.94 mmol) were added and the mixture was stirred for 5 min.Dimethylamine hydrochloride (0.27 g, 3.2 mmol) was then added at thesame temperature and the reaction was stirred for 48 h at roomtemperature. After completion, the reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by silica gel column chromatographyusing 2-3% dichloromethane in methanol as eleunt. The desired fractionswere concentrated under reduced pressure to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(rac-Cpd. No. 11F) as white solid. The enantiomers were separated bychiral preparative HPLC [chiralpak IB (4.6×250) mm]. Peak 1 (64 mg),[α]_(D) +212.3° (c 0.1, CHCl₃), R_(t)=9.727 min, ee>99% ¹H NMR (400 MHz,DMSO-d₆) δ: 8.20 (d, J=2.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.14 (d,J=8.8 Hz, 2H), 7.05 (m, 4H), 6.95 (d, J=7.2 Hz, 1H), 6.91 (d, J=7.4 Hz,2H), 6.04 (s, 1H), 5.28 (d, J=5.7 Hz, 1H), 4.7 (t, J=5.4 Hz, 1H), 4.57(d, J=13.2 Hz, 1H), 4.25 (dd, J=13.2, 5.2 Hz, 1H), 3.26 (s, 3H), 2.77(s, 3H); MS (ESI) m/z 529.35 [M+1]⁺; UPLC: 99.92%. Peak-2 (Cpd. No. 11F,68 mg), [α]_(D) −209.6° (c 0.1, CHCl₃), R_(t)=23.133 min, ee>99%. ¹H NMR(400 MHz, DMSO-d₆) δ: 8.20 (d, J=2.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H),7.13 (d, J=8.8 Hz, 2H), 7.03 (m, 4H), 6.95 (d, J=7.4 Hz, 1H), 6.91 (d,J=7.4 Hz, 2H), 6.04 (s, 1H), 5.29 (d, J=5.6 Hz, 1H), 4.73 (t, J=5.4 Hz,1H), 4.57 (d, J=13.2 Hz, 1H), 4.25 (dd, J=13.2, 5.2 Hz, 1H), 3.26 (s,3H), 2.77 (s, 3H); MS (ESI) m/z 529.34 [M+1]⁺; UPLC: 99.83%.

Example 12(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-5a-(4-(methylsulfonyl)phenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 12F)

Synthesis of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-(methylsulfonyl)phenyl)prop-2-en-1-one(3)

To a solution of 1-(5-chloro-3-hydroxypyridin-2-yl)ethan-1-one (1, 4.0g, 23.4 mmol) in methanol (20 mL), sodium hydroxide (2.8 g, 70.2 mmol)was added followed by addition of 4-(methylsulfonyl)benzaldehyde (2, 4.3g, 23.4 mmol). The reaction was heated to reflux for 30 min. Aftercompletion, the reaction mass was cooled to room temperature and dilutedwith water (20 mL). The precipitated solid was filtered, washed withwater, n-pentane and dried under vacuum to afford(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-(methylsulfonyl)phenyl)prop-2-en-1-one(3) as yellow solid. Yield: 5.3 g, 68.0%; MS (ESI) m/z 338.15[M+1]⁺.

Synthesis of7-chloro-3-hydroxy-2-(4-(methylsulfonyl)phenyl)-4H-pyrano[3,2-b]pyridin-4-one(4)

To a solution of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-(methylsulfonyl)phenyl)prop-2-en-1-one(3, 5.3 g, 15.7 mmol) in ethanol (30 mL) and dichloromethane (6 mL) at0° C., 10% aq. sodium hydroxide (4.4 g, 110.1 mmol) was added followedby the addition of 30% hydrogen peroxide (11.3 mL, 110.1 mmol). Thereaction mass was stirred for 30 min at room temperature (exotherm wasobserved). After completion, the reaction mass was cooled andneutralized to pH ˜7 by the addition of 6 M hydrogen chloride. Themixture was extracted with ethyl acetate (100 mL). The organic layer waswashed with water and brine, dried over anhydrous sodium sulfate,filtered and concentrated. The solid obtained was triturated withn-pentane and ethanol, filtered and dried under vacuum to afford7-chloro-3-hydroxy-2-(4-(methylsulfonyl)phenyl)-4H-pyrano[3,2-b]pyridin-4-one(4) as light brown solid. Yield: 0.80 g, 15.3%; MS (ESI) m/z352.13[M+1]⁺.

Synthesis of rac-methyl3-chloro-7a-hydroxy-5a-(4-(methylsulfonyl)phenyl)-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carboxylate (6)

A solution of7-chloro-3-hydroxy-2-(4-(methylsulfonyl)phenyl)-4H-pyrano[3,2-b]pyridin-4-one(4, 1.9 g, 5.4 mmol) and methyl cinnamate (5, 8.8 g, 54.1 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedunder 400 watts UV light for 8 h. After completion, solvent was removedunder reduced pressure and the residue was purified over a plug ofsilica gel eluting the compound with ethyl acetate. The desiredfractions were concentrated under reduced pressure to afford rac-methyl3-chloro-7a-hydroxy-5a-(4-(methylsulfonyl)phenyl)-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carboxylate(6) as brown solid. Yield: 2.5 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-5a-(4-(methylsulfonyl)phenyl)-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7)

The crude rac-methyl3-chloro-7a-hydroxy-5a-(4-(methylsulfonyl)phenyl)-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carboxylate(6, 2.5 g, 4.8 mmol) was suspended in methanol (30 mL) and treated with25% sodium methoxide in methanol (15 mL) followed by heating at 80° C.for 2 h. After completion, the solvent was removed under reducedpressure. The crude was diluted with ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and concentrated under reduced pressure to affordrac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-5a-(4-(methylsulfonyl)phenyl)-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7). Yield: 1.6 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-(methylsulfonyl)phenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8)

To a solution of sodium triacetoxyborohydride (3.96 g, 18.8 mmol),rac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-5a-(4-(methylsulfonyl)phenyl)-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7, 1.6 g, 3.1 mmol) in acetonitrile (30 mL), acetic acid (1.87 g, 31.2mmol) was added. The resulting mixture was stirred for 12 h at roomtemperature. After completion, the reaction mixture was partitionedbetween saturated aqueous sodium bicarbonate solution and ethyl acetate.The organic layer was separated and dried over sodium sulphate, filteredand concentrated to give crude. The crude was purified by silica gelcolumn chromatography using 2-3% dichloromethane in methanol as eluent.The desired fractions were concentrated to afford rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-(methylsulfonyl)phenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8) as brown solid. Yield: 0.6 g, 37.5%; MS (ESI) m/z 516.1[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-(methylsulfonyl)phenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-(methylsulfonyl)phenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8, 0.6 g, 1.16 mmol) in methanol, tetrahydrofuran and water (2:1:1, 12mL), lithium hydroxide (0.27 g, 11.16 mmol) was added and the reactionwas stirred for 2 h at room temperature. After completion, the reactionmass was cooled to 0° C. and acidified with 1 M hydrochloric acid to pH˜2-3. The precipitate was filtered and dried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-(methylsulfonyl)phenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9) as off white solid. Yield: 0.45 g, 77.5%; MS (ESI) m/z502.04[M+1]⁺.

Synthesis of(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-5a-(4-(methylsulfonyl)phenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 12F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-(methylsulfonyl)phenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9, 0.3 g, 0.59 mmol) in dichloromethane (8 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.28 g, 1.79 mmol),hydroxybenzotriazole (0.27 g, 1.79 mmol) and N,N-diisopropylethylamine(0.46 g, 3.59 mmol) were added and the mixture was stirred for 10 min.Dimethylamine hydrochloride (0.24 g, 2.99 mmol) was then added at thesame temperature and the reaction was stirred for 32 h at roomtemperature. After completion, the reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by silica gel column chromatographyusing 2-3% dichloromethane in methanol as eluent. The desired fractionswere concentrated under reduced pressure to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-5a-(4-(methylsulfonyl)phenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(rac-Cpd. No. 12F) as off white solid. The enantiomers were separated bychiral preparative HPLC [chiralpak IB (4.6×250) mm]. Yield: 0.16 g,(racemic mixture). Peak 1 (47 mg), [α]_(D) +196.10 (c 0.1, CHCl₃),R_(t)=8.089 min, ee>99%. 1H NMR (400 MHz, DMSO-d₆) δ: 8.21 (d, J=2.0 Hz,1H), 7.74 (d, J=2.0 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz,2H), 7.04 (t, J=7.2 Hz, 2H), 6.96 (t, J=9.6 Hz, 3H), 6.16 (bs, 1H), 5.38(bs, 1H), 4.77 (d, J=5.2 Hz, 1H), 4.64 (d, J=13.6 Hz, 1H), 4.35 (dd,J=13.2, 5.2 Hz, 1H), 3.28 (s, 3H), 3.03 (s, 3H), 2.78 (s, 3H); MS (ESI)m/z 529.35[M+1]⁺; UPLC: 99.92%. Peak-2 (Cpd. No. 12F, 44 mg), [α]_(D)−173.2° (c 0.1, CHCl₃), R_(t)=16.147 min, ee>99%. 1H NMR (400 MHz,DMSO-d₆) δ: 8.21 (d, J=2.0 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.58 (d,J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.04 (t, J=7.2 Hz, 2H), 6.96 (t,J=9.6 Hz, 3H), 6.18 (bs, 1H), 5.36 (bs, 1H), 4.77 (d, J=5.2 Hz, 1H),4.64 (d, J=13.2 Hz, 1H), 4.35 (dd, J=13.2, 5.2 Hz, 1H), 3.28 (s, 3H),3.03 (s, 3H), 2.98 (s, 3H); MS (ESI) m/z 529.34[M+1]⁺

Example 13Rac-(1R,2R,3S,3aR,8bS)-6-cyano-3a-(4-cyanophenyl)-1,8b-dihydroxy-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxamide(Cpd. No. 13F)

Synthesis of 2-(benzylthio)-4-bromobenzonitrile (3)

To a stirred suspension of sodium hydride (30.15 g, 753.7 mmol) intetrahydrofuran (1500 mL), benzyl mercaptan (2, 62.4 g, 502.6 mmol) wasadded slowly at 0° C. and stirred for 15 min.4-Bromo-2-fluorobenzonitrile (1, 100.0 g, 502.6 mmol) was added slowlyat same temperature and then reaction mixture was stirred at roomtemperature for 1 h. After completion, reaction mass was treated withsaturated ammonium chloride solution and extracted with ethyl acetate.The organic layer was separated and dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure to afford2-(benzylthio)-4-bromobenzonitrile (3) as yellow solid. Yield: 19.3 g,62%; MS (ESI) m/z 302.01[M−1]⁻.

Synthesis of 1-(2-(benzylthio)-4-bromophenyl)ethan-1-one (4)

To a solution of 2-(benzylthio)-4-bromobenzonitrile (3, 90.0 g, 297.0mmol) in tetrahydrofuran (1000 mL), 3 M methyl magnesium bromide indiethyl ether (290.4 mL, 891.0 mmol) was added drop wise at −10° C. Thereaction mass was slowly brought to room temperature and stirred for 16h. After completion, the reaction mass was acidified with saturated 6 Mhydrogen chloride solution and then extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to afford1-(2-(benzylthio)-4-bromophenyl)ethan-1-one (4) as brown solid. Yield:74.0 g, Crude

Synthesis of 1-(4-bromo-2-mercaptophenyl)ethan-1-one (5)

To a solution of aluminum trichloride (74.79 g, 562.50 mmol) in benzene(1200 mL), 1-(2-(benzylthio)-4-bromophenyl)ethan-1-one (4, 60.0 gm,187.5 mmol) was added at 0° C. The reaction mass was slowly brought toroom temperature and stirred for 2 h. After completion, the reactionmass was basified by 1 N sodium hydroxide solution to pH ˜8-9 and thenwashed with ethyl acetate. Then aqueous layer was acidified by 1 Mhydrogen chloride solution to pH ˜5-6 and then extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure to afford1-(4-bromo-2-mercaptophenyl)ethan-1-one (5) as yellow solid. Yield: 31.5g, 73.2%; MS (ESI) m/z 229.09[M−1]⁻.

Synthesis of S-(2-acetyl-5-bromophenyl) 4-bromobenzothioate (7)

To a solution of 1-(4-bromo-2-mercaptophenyl)ethan-1-one (5, 21.5 g,93.4 mmol) in dichloromethane (200 mL), triethylamine (39.2 g, 28.04mmol) and N,N-dimethylaminopyridine (1.1 g, 9.3 mmol) were added at 0°C., followed by slow addition of 4-bromobenzoyl chloride (6, 30.7 g,140.2 mmol). The reaction mixture was stirred at room temperature for 1h. After completion, reaction mass was quenched with cold water andextracted with dichloromethane. The organic layer was dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure to get the solid which was triturated with pentane to affordS-(2-acetyl-5-bromophenyl) 4-bromobenzothioate (7) as brown solid.Yield: 27.9 g, 72.4%; MS (ESI) m/z 411.04[M−1]⁻.

Synthesis of S-(5-bromo-2-(2-bromoacetyl)phenyl)-4-bromobenzothioate (8)

To a solution of S-(2-acetyl-5-bromophenyl) 4-bromobenzothioate (7, 27.0g, 67.0 mmol) in tetrahydrofuran (300 mL), trimethylphenylammoniumtribromide (33.2 g, 88.0 mmol) was added at room temperature. Thereaction mass was stirred at 60° C. for 16 h. After completion, reactionmass was cooled and water was added followed by extraction with ethylacetate. The organic layer was dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to affordS-(5-bromo-2-(2-bromoacetyl)phenyl) 4-bromobenzothioate (8) as yellowsolid. Yield: 12.5 g, crude.

Synthesis of 2-(4-bromo-2-((4-bromobenzoyl)thio)phenyl)-2-oxoethylbenzoate (10)

To a solution of benzoic acid (9, 2.98 g, 24.48 mmol) in acetone (750mL), N,N-diisopropylethylamine (3.15 g, 24.48 mmol) was added andmixture was stirred at room temperature for 15 min. The mixture wascooled to 0° C. andS-(5-Bromo-2-(2-bromoacetyl)phenyl)-4-bromobenzothioate (8, 12.0 g,24.48 mmol) was added. The reaction mass was slowly brought to roomtemperature and stirred for 2 h. After completion, the solvent wasremoved under reduced pressure and the residue was diluted with waterand extracted with dichloromethane. The organic layer was dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure. The crude was purified by column chromatography on silica gel(100-200 mesh) using 10% ethyl acetate in hexanes as eluent. The desiredfractions were concentrated under reduced pressure to afford2-(4-bromo-2-((4-bromobenzoyl)thio)phenyl)-2-oxoethyl benzoate (10) asyellow solid. Yield: 4.0 g, crude.

Synthesis of 7-bromo-2-(4-bromophenyl)-2-hydroxy-4-oxothiochroman-3-ylbenzoate (11)

To a solution of 2-(4-bromo-2-((4-bromobenzoyl)thio)phenyl)-2-oxoethylbenzoate (10, 4.0 g, 7.53 mmol) in tetrahydrofuran (250 mL), 1 M lithiumbis(trimethylsilyl)amide in tetrahydrofuran (22.5 ml, 3.0 mmol) wasadded at −78° C. The reaction mass was slowly brought to roomtemperature and stirred for 30 min. After completion, reaction mixturewas quenched with saturated ammonium chloride solution and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure to afford7-bromo-2-(4-bromophenyl)-2-hydroxy-4-oxothiochroman-3-yl benzoate (11)as brown solid. Yield: 3.2 g, crude.

Synthesis of 7-bromo-2-(4-bromophenyl)-4-oxo-4H-thiochromen-3-ylbenzoate (12)

To a solution of7-bromo-2-(4-bromophenyl)-2-hydroxy-4-oxothiochroman-3-yl benzoate (11,3.2 g, 6.2 mmol) in acetic acid (6.4 mL, 2 volumes), sulphuric acid (3.2mL, 1 volumes) was added drop wise and stirred the mixture for 4 h atroom temperature. After completion, crushed ice was added to thereaction and the precipitated solid was filtered, washed with cold waterand dried under reduced pressure to afford7-bromo-2-(4-bromophenyl)-4-oxo-4H-thiochromen-3-yl benzoate (12) asbrown solid. Yield: 3.0 g, crude.

Synthesis of 7-bromo-2-(4-bromophenyl)-3-hydroxy-4H-thiochromen-4-one(13)

To a solution of 7-bromo-2-(4-bromophenyl)-4-oxo-4H-thiochromen-3-ylbenzoate (12, 3.0 g, 5.8 mmol) in ethanol (10 mL),10% sodium hydroxidesolution (8.9 g, 2.4 mmol) was added and the reaction mixture wasstirred for 3 h at 90° C. After completion, the reaction mass was cooledto room temperature and acidified with 1 M hydrogen chloride to pH ˜6.The precipitated solid was filtered and dried under vacuum to afford7-bromo-2-(4-bromophenyl)-3-hydroxy-4H-thiochromen-4-one (13) as brownsolid. Yield: 0.8 g, 34%; MS (ESI) m/z 408.98[M−1]⁻.

Synthesis of rac-methyl(2S,3S,4S,5R)-8-bromo-2-(4-bromophenyl)-5-hydroxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanobenzo[b]thiepine-4-carboxylate(15/16)

A solution of 7-bromo-2-(4-bromophenyl)-3-hydroxy-4H-thiochromen-4-one(13, 0.8 g, 1.95 mmol) and methyl cinnamate (14, 3.16 g, 19.5 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiated at400 watts UV light for 15 h. After completion, the solvent was removedunder reduced pressure and the crude was purified by Combi-flash (12 g,RediSep column) using ethyl acetate as eluent. The desired fractionswere concentrated under reduced pressure to afford rac-methyl(2S,3S,4S,5R)-8-bromo-2-(4-bromophenyl)-5-hydroxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanobenzo[b]thiepine-4-carboxylate(15/16). Yield: 0.6 g, crude.

Synthesis of rac-methyl(2R,3S,3aR,8bS)-6-bromo-3a-(4-bromophenyl)-8b-hydroxy-1-oxo-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxylate(17)

The crude methyl(2S,3S,4S,5R)-8-bromo-2-(4-bromophenyl)-5-hydroxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanobenzo[b]thiepine-4-carboxylate(15, 16, 0.60 g) was suspended in methanol (6 mL) and treated with 25%sodium methoxide in methanol (6 mL). The mixture was then heated at 90°C. for 3 h. After completion, the solvent was removed under reducedpressure and crude was treated with ammonium chloride solution andextracted with ethyl acetate. The organic phase was dried over anhydroussodium sulphate and concentrated under reduced pressure to affordrac-methyl(2R,3S,3aR,8bS)-6-bromo-3a-(4-bromophenyl)-8b-hydroxy-1-oxo-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxylate(17). Yield: 450 mg, crude.

Synthesis of rac-methyl(1R,2R,3S,3aR,8bS)-6-bromo-3a-(4-bromophenyl)-1,8b-dihydroxy-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxylate(18)

To a solution of rac-methyl(2R,3S,3aR,8bS)-6-bromo-3a-(4-bromophenyl)-8b-hydroxy-1-oxo-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxylate(17, 0.45 g, 0.78 mmol) in acetonitrile (10.0 mL), sodiumtriacetoxyborohydride (0.99 g, 4.71 mmol) and acetic acid (0.47 mL, 7.85mmol) were added. The resulting mixture was stirred at room temperaturefor 6 h. After completion, reaction mixture was partitioned betweensaturated aqueous sodium bicarbonate solution and ethyl acetate. Theorganic layer was separated, dried over anhydrous sodium sulphate andconcentrated under reduced pressure to get crude. The crude was purifiedby Combi-flash (4 g, RediSep column) using 30-40% ethyl acetate inhexanes as eluent. The desired fractions were concentrated under reducedpressure to afford rac-methyl(1R,2R,3S,3aR,8bS)-6-bromo-3a-(4-bromophenyl)-1,8b-dihydroxy-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxylate(18). Yield: 0.12 g, 26%, MS (ESI) m/z 572.98[M−1]⁻.

Synthesis ofrac-(1R,2R,3S,3aR,8bS)-6-bromo-3a-(4-bromophenyl)-1,8b-dihydroxy-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxylic acid (19)

To a solution of rac-methyl(1R,2R,3S,3aR,8bS)-6-bromo-3a-(4-bromophenyl)-1,8b-dihydroxy-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxylate(18, 0.12 g, 0.2 mmol) in tetrahydrofuran: water (7:3, 10 mL), lithiumhydroxide (0.10 g, 4.18 mmol) was added and the reaction was stirred for6 h at room temperature. After completion, the reaction mass was cooledto 0° C. and acidified with 1 M hydrogen chloride to pH ˜3. The solidprecipitated was filtered and dried under vacuum to affordrac-(1R,2R,3S,3aR,8bS)-6-bromo-3a-(4-bromophenyl)-1,8b-dihydroxy-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxylicacid (19) as white solid. Yield: 0.10 g, 86%, MS (ESI) m/z 559.05[M−1]⁻.

Synthesis of rac-(1R,2R,3S,3aR,8bS)-6-bromo-3a-(4-bromophenyl)-1,8b-dihydroxy-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxamide(20)

To a solution of rac-(1R,2R,3S,3aR,8bS)-6-bromo-3a-(4-bromophenyl)-1,8b-dihydroxy-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxylicacid (19, 0.10 g, 0.17 mmol) in dichloromethane (10 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.133 g, 0.69 mmol),hydroxybenzotriazole (0.095 g, 0.7 mmol) and N,N-diisopropylethylamine(0.32 mL, 1.8 mmol) were added at 0° C. and stirred the mixture for 5min. Dimethylamine hydrochloride (0.10 g, 1.16 mmol) was then added atsame temperature and the reaction was stirred at room temperature for 12h. After completion, reaction mass was diluted with dichloromethane (25mL) and washed with cold water. The organic layer was separated anddried over anhydrous sodium sulphate, filtered and concentrated underreduced pressure. The crude was purified by Combi-flash (4 g, RediSepcolumn) using 50% ethyl acetate in hexanes as eluent. The appropriatefractions were concentrated under reduced pressure to affordrac-(1R,2R,3S,3aR,8bS)-6-bromo-3a-(4-bromophenyl)-1,8b-dihydroxy-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxamide(20) as white solid. Yield: 80.0 mg, 77%, MS (ESI) m/z 588.10[M+1]⁺.

Synthesis ofrac-(1R,2R,3S,3aR,8bS)-6-cyano-3a-(4-cyanophenyl)-1,8b-dihydroxy-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxamide(Cpd. No. 13F)

To a mixture ofrac-(1R,2R,3S,3aR,8bS)-6-bromo-3a-(4-bromophenyl)-1,8b-dihydroxy-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxamide(20, 0.07 g, 0.11 mmol) in dimethylformamide (2 mL) at room temperature,zinc cyanide (0.083 g, 0.71 mmol) and zinc powder (0.011 g, 0.017 mmol)were added and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino) ferrocene (0.013 g, 0.002 mmol) andtris(dibenzylideneacetone)dipalladium (0.032 g, 0.003 mmol) were addedto the above reaction and degassing was continued for another 5 minfollowed by heating the reaction at 140° C. for 3 h. After completion,the reaction was cooled to room temperature and passed through celitebed. Filtrate was concentrated under reduced pressure and treated withice-cold water, the solid precipitated was filtered and purified byCombi-flash (4 g, RediSep column) using 40% ethyl acetate in hexanes aseluent to affordrac-(1R,2R,3S,3aR,8bS)-6-cyano-3a-(4-cyanophenyl)-1,8b-dihydroxy-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2-carboxamide(Cpd. No. 13F) as white solid. Yield: 0.018 mg, 31%. MS (ESI) m/z482.38[M+1]+; UPLC 95.7%; 1H NMR (400 MHz, DMSO-d₆) δ: 7.90 (d, J=4.0Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.60-7.57 (m, 3H), 7.26 (d, J=8.4 Hz,2H), 7.07-7.06 (m, 3H), 6.78-6.76 (m, 2H), 6.08 (s, 1H), 5.91 (d, J=6.5Hz, 1H), 5.00 (dd, J=8.3, 6.8 Hz, 1H), 4.32 (d, J=12.2 Hz, 1H), 3.95(dd, J=12.0, 8.8 Hz, 1H), 3.13 (s, 3H), 2.69 (s, 3H).

Example 14Rac-(5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(Cpd. No. 14F)

Synthesis of 6-chloro-N,4-dimethoxy-N-methylnicotinamide (3)

To a solution of 6-chloro-4-methoxynicotinic acid (1, 25.0 g, 133.6mmol) in dichloromethane (300 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38.44 g,200.5 mmol), 1-hydroxybenzotriazole (30.40 g, 200.4 mmol) andN,N-diisopropylethylamine (69.8 mL, 400.8 mmol) were added at 0° C. andstirred the mixture for 5 min. N, O-dimethylhydroxylamine hydrochloride(2, 19.56 g, 200.53 mmol) was then added at same temperature and thereaction was stirred for 16 h at room temperature. After completion,reaction mass was diluted with dichloromethane and washed with coldwater. The organic layer was separated and dried over sodium sulphate,filtered and concentrated to give crude. The crude was re-crystallisedin ethanol to afford 6-chloro-N,4-dimethoxy-N-methylnicotinamide (3) aswhite solid. Yield: 19.3 g, 62%; MS (ESI) m/z 231.17 [M+1]⁺.

Synthesis of 1-(6-chloro-4-methoxypyridin-3-yl)ethan-1-one (4)

To a solution of 6-chloro-N,4-dimethoxy-N-methylnicotinamide (3, 17.0 g,73.9 mmol) in dry tetrahydrofuran (200 mL), methyl magnesium bromide(26.43 mL, 221.7 mmol) was added drop wise over a period of 30 min at 0°C. The reaction mass was slowly brought to room temperature and stirredfor 2 h. After completion, the reaction mass was treated with saturatedammonium chloride solution and then extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford1-(6-chloro-4-methoxypyridin-3-yl)ethan-1-one (4) as yellow solid.Yield: 12.0 g, 87%; MS (ESI) m/z 186.17[M+1]⁺.

Synthesis of 1-(6-chloro-4-hydroxypyridin-3-yl)ethan-1-one (5)

To a solution of 1-(6-chloro-4-methoxypyridin-3-yl)ethan-1-one (4, 10.0g, 54.0 mmol) in acetic acid (30.0 mL), 6 M hydrogen chloride (60.0 mL)was added. The reaction mixture was refluxed at 100° C. for 16 h. Aftercompletion, the reaction mass was concentrated under reduced pressureand diluted with water, cooled to 0° C. and basified with 10% NaOHsolution to pH ˜9-10 and extracted with ethyl acetate. The organic layerwas concentrated to recover starting material. The aqueous layer wascooled to 0° C. and acidified with 6 M hydrogen chloride. Theprecipitated solid was filtered and dried to afford1-(6-chloro-4-hydroxypyridin-3-yl)ethan-1-one (5) as brown solid. Yield:6.3 g, 68.4%; MS (ESI) m/z 170.08 [M−1]⁻.

Synthesis of(E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxypyridin-3-yl)prop-2-en-1-one(6)

To a solution of 1-(6-chloro-4-hydroxypyridin-3-yl)ethan-1-one (5, 5.5g, 32.0 mmol) in methanol: dichloromethane (50:20 mL), sodium hydroxide(3.84 g, 96.0 mmol) was added followed by addition of4-bromobenzaldehyde (6.5 g, 35.0 mmol) and the reaction mixture washeated at 90° C. for 1 h. After completion, reaction mass was cooled andobtained solid was filtered, washed with water and dried under vacuum toafford of(E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxypyridin-3-yl)prop-2-en-1-one(6) as yellow solid. Yield: 10.5 g, 95%; MS (ESI) m/z 338.08 [M+1]⁺.

Synthesis of2-(4-bromophenyl)-7-chloro-3-hydroxy-4H-pyrano[3,2-c]pyridin-4-one (7)

To a solution of(E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxypyridin-3-yl)prop-2-en-1-one(6, 10.0 g, 29.0 mmol) in methanol (150 mL), 10% sodium hydroxide (36mL, 88.0 mmol) was added followed by addition of hydrogen peroxide (6.57mL, 58.0 mmol) at room temperature. The reaction mass was stirred for 1h (exotherm was observed). After completion, reaction mass was cooledand neutralized with 6 M hydrogen chloride to pH ˜7. The precipitatedsolid was filtered and dried under vacuum to afford2-(4-bromophenyl)-7-chloro-3-hydroxy-4H-pyrano[3,2-c]pyridin-4-one (7)as yellow solid. Yield: 3.1 g, 30%; MS (ESI) m/z 350.08[M−1]⁻.

Synthesis of rac-methyl(2S,3S,4S,5R)-2-(4-bromophenyl)-8-chloro-5-hydroxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate(9)

A solution of2-(4-bromophenyl)-7-chloro-3-hydroxy-4H-pyrano[3,2-c]pyridin-4-one (7,3.1 g, 8.5 mmol) and methyl cinnamate (8, 13.82 g, 85.0 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedfor 24 h under 400 watts UV light. After completion, the solvent wasremoved under reduced pressure and the residue was purified over a plugof silica gel eluting the compound with ethyl acetate. The desiredfractions were concentrated under reduced pressure to afford rac-methyl(2S,3S,4S,5R)-2-(4-bromophenyl)-8-chloro-5-hydroxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate(9). Yield: 3.1 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(10)

The crude rac-methyl(2S,3S,4S,5R)-2-(4-bromophenyl)-8-chloro-5-hydroxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate(9, 3.1 g) was suspended in methanol (30 mL) and treated with sodiummethoxide (25% in methanol, 20 mL) and heated the mixture to 90° C. for3 h. After completion, the solvent was removed under reduced pressure,diluted the mixture with ammonium chloride solution and extracted withethyl acetate. The organic phase was separated, dried over sodiumsulphate and concentrated under reduced pressure to afford rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(10). Yield: 2.2 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(11)

To a solution of sodium triacetoxyborohydride (5.2 g, 24.0 mmol),rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(10, 2.1 g) in acetonitrile (50 mL), acetic acid (2.4 mL, 40.0 mmol) wasadded. The resulting mixture was stirred for 4 h at room temperature.After completion, reaction mixture was partitioned between saturatedaqueous sodium bicarbonate solution and ethyl acetate. The organic layerwas separated, dried over sodium sulphate and concentrated under reducedpressure to get the crude. The crude was purified by silica gel columnchromatography eluting with 30% ethyl acetate in hexanes. The desiredfractions were concentrated to afford rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(11) as off white solid. Yield: 1.21 g, 57.6%; MS (ESI) m/z 516.22[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (12)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(11, 1.2 g, 2.3 mmol) in tetrahydrofuran and water (3:1, 15 mL), lithiumhydroxide (0.55 g, 23.0 mmol) was added and the reaction was stirred for16 h at room temperature. After completion, the reaction mass was cooledto 0° C. and acidified with 1M hydrogen chloride to pH ˜3. Theprecipitated solid was filtered and dried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (12) as off white solid. Yield: 1.05 g, 90%; MS (ESI) m/z502.06[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(13)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (12, 0.7 g, 13.9 mmol) in dichloromethane (50 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.8 g, 4.17mmol), 1-hydroxybenzotriazole (0.63 g, 4.17 mmol) andN,N-diisopropylethylamine (1.43 mL, 8.3 mmol) were added at 0° C. andstirred the mixture for 5 min. Dimethylamine hydrochloride (0.56 g, 6.9mmol) was then added at same temperature and the mixture was stirred for16 h at 40° C. After completion, reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by silica gel column chromatographyeluting with 70% ethyl acetate in hexanes. The desired fractions wereconcentrated to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(13) as white solid. Yield: 0.52 g, 71%; MS (ESI) m/z 523.21 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(Cpd. No. 14F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(13, 0.5 g, 0.94 mmol) in N,N-dimethylformamide (10.0 mL), zinc cyanide(0.66 g, 5.6 mmol) and zinc (0.007 g, 0.1 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.013 g, 0.018 mmol),tris(dibenzylideneacetone)dipalladium (0.026 g, 0.028 mmol) were addedto the reaction and degassing was continued for another 5 min. Thereaction mixture was heated at 150° C. for 2 h. After completion, thereaction was cooled to room temperature and passed through celite bed.The filtrate was diluted with ethyl acetate and washed with water. Theorganic layer was separated, dried over sodium sulphate and concentratedunder reduced pressure to get the crude. The crude was purified bysilica gel column chromatography eluting with 70% ethyl acetate inhexanes. The desired fractions were concentrated under reduced pressureto affordrac-(5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(Cpd. No. 14F) as white solid. Yield: 0.15 g, 34%; MS (ESI) m/z 467.20[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 1H), 7.97 (s, 1H), 7.60 (d,J=8.8 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 7.06-6.98 (m, 3H), 6.84 (d, J=6.8Hz, 2H), 6.13 (s, 1H), 5.98 (d, J=6.4 Hz, 1H), 4.95 (t, J=6.8 Hz, 1H),4.27-4.14 (m, 2H), 3.23 (s, 3H), 2.73 (s, 3H).

Example 15Rac-(4bS,5R,6R,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-2-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxamide(Cpd. No. 15F)

Synthesis of 2-chloro-6-methoxynicotinic acid (2)

To a suspension of 2,6-dichloronicotinic acid (1, 20.0 g, 105.2 mmol) inmethanol (250 mL) under nitrogen, potassium tert-butoxide (35.0 g, 316.0mol) was added at room temperature. The reaction mixture was allowed tostir at 80° C. for 24 h. After completion, solvent was removed underreduced pressure and crude was treated with 6 M hydrogen chloride.Precipitated solid was filtered and dried under vacuum to afford2-chloro-6-methoxynicotinic acid (2) as white solid. Yield: 20.0 g,crude; MS (ESI) m/z 188.06[M+1]⁺.

Synthesis of 2-chloro-N,6-dimethoxy-N-methylnicotinamide (4)

To a solution of 2-chloro-6-methoxynicotinic acid (2, 20.0 g, 107.52mmol) in dichloromethane (400 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30.6 g,161.0 mmol), 1-hydroxybenzotriazole (21.6 g, 161.0 mmol) andN,N-diisopropylethylamine (46.6 mL, 322.5 mmol) were added at 0° C. andstirred the mixture for 5 min. N,O-dimethylhydroxylamine hydrochloride(3, 12.4 g, 129.0 mmol) was then added at same temperature and thereaction was stirred at room temperature for 4 h. After completion,reaction mass was diluted with dichloromethane and washed with coldwater. The organic layer was separated and dried over anhydrous sodiumsulphate, filtered and concentrated to afford2-chloro-N,6-dimethoxy-N-methylnicotinamide (4) as yellow solid. Yield:18.0 g, 58.3%; MS (ESI) m/z 231.15[M+1]⁺.

Synthesis of 1-(2-chloro-6-methoxypyridin-3-yl)ethan-1-one (5)

To a solution of 2-chloro-N,6-dimethoxy-N-methylnicotinamide (4, 18.0 g,78.2 mmol) in dry tetrahydrofuran (200 mL), 3 M methyl magnesium bromidein diethyl ether (52.0 mL, 156.5 mmol) was added drop wise over a periodof 30 min at 0° C. The reaction mass was slowly brought to roomtemperature and stirred for 2 h. After completion, the reaction mass wastreated with saturated ammonium chloride solution and then extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure to afford1-(2-chloro-6-methoxypyridin-3-yl)ethan-1-one (5) as yellow solid.Yield: 14.0 g, crude; MS (ESI) m/z 186.14[M+1]⁺.

Synthesis ofl-(6-methoxy-2-((4-methoxybenzyl)oxy)pyridin-3-yl)ethan-1-one (7)

To a solution of 1-(2-chloro-6-methoxypyridin-3-yl)ethan-1-one (5, 14.0g, 75.6 mmol) in tetrahydrofuran (100 mL) under nitrogen, sodium hydride(4.5 g, 113.4 mol) was added at 0° C. and stirred for 10 min.4-methoxybenzyl alcohol (6, 11.0 mL, 75.6 mmol) was added drop wise overa period of 30 min at 0° C. and stirred at room temperature for 2 h.After completion, the reaction mass was diluted with water (200 mL) andthen extracted with ethyl acetate (2×150 mL). The organic layer wasdried over anhydrous sodium sulphate, filtered and concentrated underreduced pressure to get the crude. The crude was purified by columnchromatography on silica gel (100-200 mesh) using 20% ethyl acetate inhexanes as eluent. The desired fractions were concentrated under reducedpressure to afford1-(6-methoxy-2-((4-methoxybenzyl)oxy)pyridin-3-yl)ethan-1-one (7) asyellow solid. Yield: 10.5 g, 48.3%; MS (ESI) m/z 288.23[M+1]⁺.

Synthesis of 3-acetyl-6-methoxypyridin-2(1H)-one (8)

To a cool solution of1-(6-methoxy-2-((4-methoxybenzyl)oxy)pyridin-3-yl)ethan-1-one (7, 10.5g, 36.6 mmol) in dichloromethane (100 mL), trifluoroacetic acid (2.0 mL)was added at 0° C. and the reaction mixture was stirred at roomtemperature for 2 h. After completion, saturated solution of sodiumbicarbonate was added to the reaction mixture and extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure to afford3-acetyl-6-methoxypyridin-2(1H)-one (8) as yellow solid. Yield: 5.0 g,crude; MS (ESI) m/z 168.17[M+1]⁺.

Synthesis of(E)-3-(3-(4-bromophenyl)acryloyl)-6-methoxypyridin-2(1H)-one (10)

To a solution of 3-acetyl-6-methoxypyridin-2(1H)-one (8, 4.5 g, 26.4mmol) in methanol (30.0 mL), sodium hydroxide (3.17 g, 79.4 mmol) and4-bromobenzaldehyde (9, 5.3 g, 29.1 mmol) were added. The reactionmixture was heated at 80° C. for 2 h. After completion, reaction masswas cooled and obtained solid was filtered, washed with water and driedunder vacuum to afford(E)-3-(3-(4-bromophenyl)acryloyl)-6-methoxypyridin-2(1H)-one (10) asyellow solid. Yield: 8.5 g, crude; MS (ESI) m/z 332.11[M−1]⁻.

Synthesis of2-(4-bromophenyl)-3-hydroxy-7-methoxy-4H-pyrano[2,3-b]pyridin-4-one (11)

To a solution(E)-3-(3-(4-bromophenyl)acryloyl)-6-methoxypyridin-2(1H)-one (10, 6 g,17.8 mmol) in ethanol/dichloromethane (1:1, 200 mL), sodium hydroxide(10%, 50 mL, 124.6 mmol) was added followed by addition of 30% hydrogenperoxide (14.1 mL, 124.6 mmol) at room temperature. The reaction masswas stirred for 2 h (excessive exotherm was observed so precaution mustbe taken). After completion, reaction mass was cooled to 0° C. and pHwas adjusted to 8 using 6 M hydrochloric acid. The solvents were removedunder reduced pressure and solid was filtered. The solid was suspendedin ethanol and neutralized by addition of 6 M hydrogen chloride (pH ˜6)at 0° C. The precipitated solid was filtered and dried under vacuum toafford2-(4-bromophenyl)-3-hydroxy-7-methoxy-4H-pyrano[2,3-b]pyridin-4-one (11)as yellow solid. Yield: 3.2 g, 41%; MS (ESI) m/z 348.16[M+1]⁺.

Synthesis of rac-methyl(2S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-8-methoxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-b]pyridine-4-carboxylate(13/14)

A solution of2-(4-bromophenyl)-3-hydroxy-7-methoxy-4H-pyrano[2,3-b]pyridin-4-one (11,3.0 g, 8.6 mmol) and methyl cinnamate (12, 1.4 g, 86.4 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedfor 16 h under 400 watts UV light. After completion, the solvent wasremoved under reduced pressure and the residue was purified byCombi-flash (12 g, RediSep) using ethyl acetate as eluent. The desiredfractions were concentrated under reduced pressure to afford rac-methyl(2S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-8-methoxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-b]pyridine-4-carboxylate(13/14) as yellow solid. Yield: 1.3 g, crude. MS(ESI) m/z 508.33[M−1]⁻.

Synthesis of rac-methyl(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-2-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxylate(15)

The crude rac-methyl(2S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-8-methoxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-b]pyridine-4-carboxylate(13/14, 1.3 g) was suspended in methanol (13.0 mL) and treated withsodium methoxide (25% in methanol, 13.0 mL) and heated the mixture to80° C. for 2 h. After completion, the solvent was removed under reducedpressure and the reaction was diluted with ammonium chloride solutionand extracted with ethyl acetate. The organic phase was separated, driedover anhydrous sodium sulphate, filtered and concentrated under reducedpressure to afford rac-methyl(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-2-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxylate(15) as brown solid. Yield: 1.1 g, crude; MS (ESI) m/z 508.33[M−1]⁻.

Synthesis of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-2-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxylate(16)

To a solution of rac-methyl(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-2-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxylate(15, 1.0 g, 2.1 mmol) in acetonitrile (20.0 mL), sodiumtriacetoxyborohydride (2.7 g, 12.9 mmol) and acetic acid (1.23 mL, 22.0mmol) were added. The resulting mixture was stirred for 4 h at roomtemperature. After completion, reaction mixture was partitioned betweensaturated aqueous sodium bicarbonate solution and ethyl acetate. Theorganic layer was separated, dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to afford rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-2-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxylate(16) as white solid. Yield: 120 mg, 12%; MS (ESI) m/z 512.32[M+1]⁺.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-2-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxylicacid (17)

To a solution of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-2-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxylate(16, 110 mg, 0.21 mmol) in methanol and water (2:1, 6.0 mL), lithiumhydroxide (20.0 mg, 0.86 mmol) was added and the reaction was stirredfor 16 h at room temperature. After completion, the reaction mass wascooled to 0° C. and acidified with 1 M hydrogen chloride to pH ˜3. Theprecipitated solid was filtered and dried under vacuum to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-2-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxylicacid (17) as brown solid. Yield: 100 mg, 93%; MS (ESI) m/z 496.16[M−1]⁻.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-2-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxamide(18)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-2-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxylicacid (17, 100 mg, 0.20 mmol) in dichloromethane (10.0 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96.0 mg,0.50 mmol), 1-hydroxybenzotriazole (76.0 mg, 0.50 mmol) andN,N-diisopropylethylamine (0.213 mL, 1.2 mmol) were added at 0° C. andstirred the mixture for 5 min. Dimethylamine hydrochloride (81.0 mg, 1.0mmol) was then added at same temperature and the mixture was stirred for6 h at room temperature. After completion, reaction mass was dilutedwith dichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by Combi-flash (4 g,RediSep) using 70% ethyl acetate in hexanes as eluent. The desiredfractions were concentrated under reduced pressure to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-2-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxamide(18) as off white solid. Yield: 40.0 mg, 37.9%; MS (ESI) m/z525.28[M+1]⁺.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-2-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxamide(Cpd. No. 15F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-2-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxamide(18, 40.0 mg, 0.076 mmol) in N,N-dimethylformamide (5.0 mL), zinccyanide (18.0 mg, 0.152 mmol) and zinc (25.0 mg, 0.38 mmol) were addedat room temperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (4.0 mg, 0.015 mmol),tris(dibenzylideneacetone) dipalladium (7.1 mg, 0.015 mmol) were addedto the reaction and degassing was continued for another 5 min. Thereaction mixture was heated at 140° C. for 6 h. After completion, thereaction was cooled to room temperature and passed through celite bed.The filtrate was diluted with ethyl acetate and washed with water. Theorganic layer was separated, dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to get the crude. Thecrude was purified by reverse phase HPLC and the desired fractions wereconcentrated under reduced pressure to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-2-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6-carboxamide(Cpd. No. 15F) as off white solid. Yield: 8.0 mg, 23%; MS (ESI) m/z472.44[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.75 (d, J=8.0 Hz, 1H), 7.58(d, J=8.4 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 7.06-6.97 (m, 3H), 6.85 (d,J=7.12 Hz, 2H), 6.46 (d, J=8.0 Hz, 1H), 5.69 (d, J=6.0 Hz, 1H), 5.57 (s,1H), 4.92 (t, J=7.7 Hz, 1H), 4.26 (d, J=13.1 Hz, 1H), 4.12 (dd, J=13.0,8.0 Hz, 1H), 3.88 (s, 3H), 3.22 (s, 3H), 2.72 (s, 3H).

Example 16(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 16F)

Synthesis of 4-(difluoromethyl)benzaldehyde (2)

To a solution of 1-bromo-4-(difluoromethyl)benzene (1, 20.0 g, 96.6mmol) in dry tetrahydrofuran (200 mL), n-butyl lithium in hexane (2.5 M,38.6 mL, 96.6 mmol) was added drop wise over a period of 30 min at −78°C. The reaction mass was stirred for 1 h at −78° C. andN,N-dimethylformamide (35.3 mL, 579.6 mmol) was added at sametemperature and reaction was stirred for 1 h. After completion, thereaction mass was brought to 0° C. and treated with saturated ammoniumchloride solution and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulphate, filtered and concentratedunder reduced pressure. The crude was purified by Combi-flash (12 g,RediSep column) using 2% ethyl acetate in hexanes as eluent. The desiredfraction were concentrated below 30° C. under reduced pressure to afford4-(difluoromethyl)benzaldehyde (2) as light yellow liquid (Used freshlyprepared compound, highly unstable). Yield: 9.0 g, 59.7%; MS (ESI) m/z:poor ionization.

Synthesis of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-(difluoromethyl)phenyl)prop-2-en-1-one(4)

To a solution of 1-(5-chloro-3-hydroxypyridin-2-yl)ethan-1-one (3, 10.4g, 60.8 mmol) in methanol (50 mL), sodium hydroxide (7.3 g, 182.4 mmol)and 4-(difluoromethyl)benzaldehyde (2, 9.5 g, 60.8 mmol) were added andthe reaction mixture was heated at 90° C. for 1 h. After completion,reaction mass was cooled and obtained solid was filtered, washed withwater and dried under vacuum to afford(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-(difluoromethyl)phenyl)prop-2-en-1-one(4) as yellow solid. Yield: 20.0 g, crude; MS (ESI) m/z 308.3[M−1]⁻.

Synthesis of7-chloro-2-(4-(difluoromethyl)phenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one(5)

To a solution of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-(difluoromethyl)phenyl)prop-2-en-1-one(4, 20.0 g, 64.7 mmol) in ethanol:dichloromethane (150 mL), 10% sodiumhydroxide (129 mL, 323.6 mmol) was added followed by addition ofhydrogen peroxide (26.5 mL, 226.4 mmol) at room temperature. Thereaction mass was stirred for 1 h (exotherm was observed). Aftercompletion, reaction mixture was cooled and neutralized with 6 Mhydrogen chloride to pH ˜7. The solvents were distilled off andprecipitated solid was filtered and dried under vacuum to afford7-chloro-2-(4-(difluoromethyl)phenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one(5) as yellow solid. Yield: 3.0 g, 13%; MS (ESI) m/z 322.17[M−1]⁻.

Synthesis of rac-methyl(6S,7S,8S,9R)-3-chloro-6-(4-(difluoromethyl)phenyl)-9-hydroxy-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(7/8)

A solution of7-chloro-2-(4-(difluoromethyl)phenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one(5, 3.0 g, 8.5 mmol) and methyl cinnamate (6, 13.82 g, 85.0 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedfor 16 h under 400 watts UV light. After completion, the solvent wasremoved under reduced pressure and the crude was purified by Combi-flash(12 g, RediSep column) using ethyl acetate as eluent. The desiredfractions were concentrated under reduced pressure to afford rac-methyl(6S,7S,8S,9R)-3-chloro-6-(4-(difluoromethyl)phenyl)-9-hydroxy-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(7/8) as brown solid. Yield: 3.0 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(9)

The crude methyl(6S,7S,8S,9R)-3-chloro-6-(4-(difluoromethyl)phenyl)-9-hydroxy-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(7, 8, 3.0 g) was suspended in methanol (30 mL) and treated with sodiummethoxide (25% in methanol, 25 mL) and heated the mixture to 90° C. for3 h. After completion, the solvent was removed under reduced pressureand mixture was diluted with ammonium chloride solution and extractedwith ethyl acetate. The organic phase was separated, dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure to afford rac-methyl(5aR,6S,7R,8aR)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(9) as brown solid. Yield: 2.5 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(10)

To a solution of sodium triacetoxyborohydride (5.2 g, 24.0 mmol), methyl(5aR,6S,7R,8aR)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(9, 2.5 g) in acetonitrile (50 mL), acetic acid (2.4 mL, 40.0 mmol) wasadded. The resulting mixture was stirred at room temperature for 4 h.After completion, reaction mixture was partitioned between saturatedaqueous sodium bicarbonate solution and ethyl acetate. The organic layerwas separated, dried over sodium sulphate and concentrated under reducedpressure to get the crude. The crude was purified by Combi-flash (12 g,RediSep) using 30% ethyl acetate in hexanes as eluent. The desiredfractions were concentrated under reduced pressure to afford rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(10) as off white solid. Yield: 1.0 g, 33%; MS (ESI) m/z 486.29[M−1]⁻.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (11)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(10, 1.2 g, 2.3 mmol) in methanol and water (3:1, 16 mL), lithiumhydroxide (0.55 g, 23.0 mmol) was added and the reaction was stirred atroom temperature for 16 h. After completion, the reaction mass wascooled to 0° C. and acidified with 1 M hydrogen chloride to pH ˜3. Theprecipitated solid was filtered and dried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (11) as off yellow solid. Yield: 1.05 g, 93%; MS (ESI) m/z472.2[M−1]⁻.

Synthesis of(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 16F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (11, 0.6 g, 13.9 mmol) in dichloromethane (50 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.72 g, 3.7mmol), 1-hydroxybenzotriazole (0.513 g, 6.33 mmol) andN,N-diisopropylethylamine (1.34 mL, 7.59 mmol) were added at 0° C. andstirred the mixture for 5 min. Dimethylamine hydrochloride (0.514 g,6.33 mmol) was then added at same temperature and the mixture wasstirred for 16 h at 40° C. After completion, reaction mass was dilutedwith dichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by Combi-flash (4 g,RediSep) using 70% ethyl acetate in hexanes as eluent. The desiredfractions were concentrated under reduced pressure to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(rac-Cpd. No. 16F) as white solid. The enantiomers were separated bychiral preparative HPLC [chiralpak ID (4.6×250) mm]. Yield: 400 mg,63.5%; Peak 1 (116 mg), [α]_(D) +218.2° (c 0.25, CHCl₃), R_(t)=8.37 min,ee>99%; MS (ESI) m/z 501.40[M+1]⁺; UPLC: 99.38%; 1H NMR (400 MHz,DMSO-d₆) δ 8.20 (d, J=2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.28-7.22 (m,4H), 7.03-6.91 (m, 5H), 6.85 (t, J=56.0 Hz, 1H), 6.06 (s, 1H), 5.30 (d,J=5.6 Hz, 1H), 4.76 (t, J=5.6 Hz, 1H), 4.60 (d, J=13.2 Hz, 1H), 4.30(dd, J=13.2, 5.2 Hz, 1H), 3.28 (s, 3H), 2.78 (s, 3H); Peak-2 (Cpd. No.16F, 129 mg), [α]_(D) −190° (c 0.28, CHCl₃), R_(t)=18.28 min, ee>99%; MS(ESI) m/z 501.40[M+1]⁺; UPLC: 99.29%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.20(d, J=2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.28 (dd, J=16.8 Hz, 8.4 Hz,4H), 7.03-6.91 (m, 5H), 6.85 (t, J=56.0 Hz, 1H), 6.06 (s, 1H), 5.30 (d,J=5.6 Hz, 1H), 4.76 (t, J=5.6 Hz, 1H), 4.60 (d, J=13.2 Hz, 1H), 4.30(dd, J=13.2, 5.2 Hz, 1H), 3.28 (s, 3H), 2.79 (s, 3H).

Example 17(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(4-(trifluoromethoxy)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 17F)

Synthesis of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one(3)

To a solution of 1-(5-chloro-3-hydroxypyridin-2-yl)ethan-1-one (1, 7.0g, 40.7 mmol) and 4-(trifluoromethoxy)benzaldehyde (2, 7.75 g, 40.7mmol) in methanol (35 mL), sodium hydroxide (4.89 g, 122.3 mmol) wasadded and the mixture was heated to refluxed for 30 min. Aftercompletion, the reaction mass was cooled to room temperature and dilutedwith water (50 mL). The precipitated solid was filtered, washed withwater, n-pentane and dried under vacuum to afford(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one(3) as yellow solid. Yield: 7.1 g, 50.0%; MS (ESI) m/z 342.18[M−1]⁻.

Synthesis of7-chloro-3-hydroxy-2-(4-(trifluoromethoxy)phenyl)-4H-pyrano[3,2-b]pyridin-4-one(4)

To a solution of(E)-1-(5-chloro-3-hydroxypyridin-2-yl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one(3, 5.0 g, 14.5 mmol) in ethanol (50 mL) at 0° C., 10% aqueous sodiumhydroxide (4.01 g, 101.5 mmol) was added followed by the addition of 30%aqueous hydrogen peroxide (11.15 mL, 101.5 mmol). The reaction mass wasstirred for 30 min at room temperature (exotherm was observed). Aftercompletion, the reaction mass was cooled and neutralized by the additionof 6 M hydrogen chloride to pH ˜7. The solid obtained was filtered,washed with ethanol, pentane and dried under vacuum to afford7-chloro-3-hydroxy-2-(4-(trifluoromethoxy)phenyl)-4H-pyrano[3,2-b]pyridin-4-one(4) as white solid. Yield: 2.8 g, 51%; MS (ESI) m/z 356.14[M+1]⁺.

Synthesis of rac-methyl(7S,8S,9R)-3-chloro-9-hydroxy-10-oxo-7-phenyl-6-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate (6/6a)

A solution of7-chloro-3-hydroxy-2-(4-(trifluoromethoxy)phenyl)-4H-pyrano[3,2-b]pyridin-4-one(4, 2.8 g, 7.8 mmol) and methyl cinnamate (5, 12.69 g, 7.8 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedunder 400 watts UV light for 24 h. After completion, solvent was removedunder reduced pressure and the residue was purified over a plug ofsilica gel eluting the compound with 5% methanol in dichloromethane. Thedesired fractions were concentrated under reduced pressure to affordrac-methyl(7S,8S,9R)-3-chloro-9-hydroxy-10-oxo-7-phenyl-6-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(6/6a) as brown solid. Yield: 3.0 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a-(4-(trifluoromethoxy)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7)

The crude rac-methyl(7S,8S,9R)-3-chloro-9-hydroxy-10-oxo-7-phenyl-6-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(6/6a, 3.0 g, 5.7 mmol) was suspended in methanol (60 mL) and treatedwith 25% sodium methoxide in methanol (12.4 mL). The reaction was heatedat 80° C. for 4 h. After completion, the solvent was removed underreduced pressure. The crude was diluted with ammonium chloride solutionand extracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and concentrated under reduced pressure to affordrac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a-(4-(trifluoromethoxy)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7) as brown solid. Yield: 3.0 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(4-(trifluoromethoxy)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8)

A solution of rac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a-(4-(trifluoromethoxy)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7, 3.0 g, 5.7 mmol) in acetonitrile (60 mL) was cooled at 0° C., tothis solution acetic acid (3.46 g, 57.7 mmol) and sodiumtriacetoxyborohydride (7.3 g, 34.6 mmol) were added. The resultingmixture was stirred for 12 h at room temperature. After completion, thereaction mixture was partitioned between saturated aqueous sodiumbicarbonate solution and ethyl acetate. The organic layer was separatedand dried over sodium sulphate, filtered and concentrated to give crude.The crude was purified by silica gel column chromatography using 2-3% inmethanol in dichloromethane as eluent. The desired fractions wereconcentrated to afford rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(4-(trifluoromethoxy)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8) as white solid. Yield: 0.6 g, 20.0%; MS (ESI) m/z 522.2[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(4-(trifluoromethoxy)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(4-(trifluoromethoxy)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8, 0.6 g, 1.15 mmol) in methanol, tetrahydrofuran and water (2:1:1, 12mL), lithium hydroxide (0.27 g, 11.5 mmol) was added and the reactionwas stirred for 6 h at room temperature. After completion, the reactionmass was concentrated and cooled to 0° C. and acidified with 1 Mhydrochloric acid to pH ˜2-3. The precipitated solid was filtered anddried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(4-(trifluoromethoxy)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9) as off white solid. Yield: 0.45 g, 77%; MS (ESI) m/z506.19[M−1]⁻.

Synthesis of(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(4-(trifluoromethoxy)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 17F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-5a-(4-(trifluoromethoxy)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9, 0.3 g, 0.59 mmol) in dichloromethane (10 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.275 g, 1.77 mmol),hydroxybenzotriazole (0.271 g, 1.77 mmol) and N,N-diisopropylethylamine(0.58 mL, 3.54 mmol) were added and the mixture was stirred for 5 min.Dimethylamine hydrochloride (0.241 g, 2.95 mmol) was then added at thesame temperature and the mixture was stirred for 16 h at roomtemperature. After completion, the reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by silica gel column chromatographyusing 2-3% methanol in dichloromethane as eluent. The desired fractionswere concentrated to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(4-(trifluoromethoxy)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(rac-Cpd. No. 17F) as off white solid. The enantiomers were separated bychiral preparative HPLC [chiralpak IB (4.6×250) mm].Yield: 0.15 g,(racemic mixture). Peak 1 (79 mg), [α]_(D) +211° (c 0.1, CHCl₃),R_(t)=5.982 min, ee>99%. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.20 (d, J=2.0 Hz,1H), 7.71 (d, J=2.0 Hz, 1H), 7.24 (d, J=8.8 Hz, 2H), 7.04-6.98 (m, 4H),6.94 (t, J=7.2 Hz, 1H), 6.89 (d, J=7.6 Hz, 2H), 6.10 (s, 1H), 5.31 (d,J=5.6 Hz, 1H), 4.76 (t, J=5.4 Hz, 1H), 4.55 (d, J=13.6 Hz, 1H), 4.25(dd, J=13.2, 5.2 Hz, 1H), 3.26 (s, 3H), 2.77 (s, 3H); MS (ESI) m/z535.36 [M+1]⁺; UPLC: 98.9%. Peak-2 (Cpd. No. 17F, 67 mg), [α]_(D)−217.4° (c 0.1, CHCl₃), R_(t)=12.093 min, ee>99%. ¹H NMR (400 MHz,DMSO-d₆) δ 8.20 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.24 (d,J=8.8 Hz, 2H), 7.04-6.98 (m, 4H), 6.95 (t, J=6.8 Hz, 1H), 6.89 (d, J=7.6Hz, 2H), 6.10 (s, 1H), 5.31 (d, J=5.6 Hz, 1H), 4.76 (t, J=5.4 Hz, 1H),4.55 (d, J=13.2 Hz, 1H), 4.25 (dd, J=13.2, 5.2 Hz, 1H), 3.26 (s, 3H),2.77 (s, 3H); MS (ESI) m/z 535.39[M+1]⁺; UPLC: 99.57%.

Example 18(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 18F)

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(1, 0.45 g, 0.87 mmol) in N,N-dimethylformamide (5 mL), zinc cyanide(0.113 g, 0.96 mmol) and zinc (0.28 g, 0.43 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.012 g, 0.017 mmol),tris(dibenzylideneacetone)dipalladium (0.023 g, 0.026 mmol) were addedto the reaction and degassing was continued for 5 min. The reactionmixture was heated at 125° C. for 3 h. After completion, the reactionwas cooled to room temperature and passed through celite bed. Thefiltrate was concentrated to get the crude. The crude was purified byCombi-flash (12 g, RediSep column) using 70% ethyl acetate in hexanes aseluent. The desired fractions were concentrated under reduced pressureto afford rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2) as white solid. Yield: 0.31 g, 77.5%; MS (ESI) m/z 463.15[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (3)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2, 0.3 g, 0.649 mmol) in methanol and water (3:1, 10 mL), lithiumhydroxide (0.077 g, 3.246 mmol) was added and the reaction was stirredfor 6 h at room temperature. After completion, the reaction mass wascooled to 0° C. and acidified with 5% citric acid to pH ˜6. Theprecipitated solid was filtered and dried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (3) as white solid. Yield: 0.21 g, 72.4%; MS (ESI) m/z 449.0[M+1]⁺.

Synthesis of(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 18F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (3, 0.18 g, 0.401 mmol) in dichloromethane (5 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16 g,0.803 mmol), 1-hydroxybenzotriazole (0.108 g, 0.803 mmol) andN,N-diisopropylethylamine (0.2 mL, 1.20 mmol) were added at 0° C. andstirred the mixture for 5 min. Ammonium chloride (0.21 g, 4.01 mmol) wasthen added at same temperature and the mixture was stirred at roomtemperature for 16 h. After completion, reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by Combi-flash (4 g,RediSep column) using 70% ethyl acetate in hexanes as eluent. Thedesired fractions were concentrated under reduced pressure to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(rac-Cpd. No. 18F) as off white solid. Yield: 0.14 g, 78.2%; MS (ESI)m/z 448.12[M+1]⁺. The enantiomers were separated by chiral preparativeHPLC [chiralpak IB (4.6×250) mm]. Yield: 140 mg, 78%; Peak-1 (Cpd. No.18F, 5 mg); [α]_(D) −184.2° (c 0.27, DMSO); R_(t)=6.41 min, ee>99%; MS(ESI) m/z 448.38[M+1]⁺; UPLC 97.6%; 1H NMR (400 MHz, DMSO-d₆) δ 8.20 (d,J=1.8 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.25 (d,J=8.4 Hz, 2H), 7.10-6.96 (m, 5H), 6.16 (s, 1H), 5.31 (d, J=4.5 Hz, 1H),4.58-4.55 (m, 1H), 3.97 (dd, J=14.0, 4.1 Hz, 1H). Peak-2 (7 mg); [α]_(D)+128.8° (c 0.26, DMSO); R_(t)=11.06 min, ee>99%; MS (ESI) m/z448.37[M+1]⁺; UPLC 99.2%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (d, J=1.9 Hz,1H), 7.70 (d, J=1.9 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz,2H), 7.09-6.96 (m, 5H), 6.16 (s, 1H), 5.31 (d, J=4.5 Hz, 1H), 4.57 (m,J=7.8 Hz, 2H), 3.97 (dd, J=13.8, 4.2 Hz, 1H).

Example 19Rac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(Cpd. No. 19F)

Synthesis of 3-bromo-2-methoxypyridin-4-amine (2)

To a solution of 2-methoxypyridin-4-amine (1, 20.0 g, 161.2 mmol) indichloromethane (200 mL) at 0° C., N-bromo succinimide (26.6 g, 161.2mmol) was added and the reaction mixture was stirred at 30° C. for 30min. After completion, the mixture was quenched with ice cold water (100mL) and the reaction mass was extracted with dichloromethane (300 mL).The organic layer was washed with water and brine, dried over anhydroussodium sulfate, filtered and concentrated. The crude was triturated withn-pentane and diethyl ether to afford 3-bromo-2-methoxypyridin-4-amine(2) as yellow solid. Yield: 30.0 g, 92%; MS (ESI) m/z 203.09[M+1]⁺.

Synthesis of 1-(4-amino-2-methoxypyridin-3-yl)ethan-1-one (3)

To a solution of 3-bromo-2-methoxypyridin-4-amine (2, 25.0 g, 123.7mmol) in toluene (250 mL), tributyl(1-ethoxyvinyl)stannane (2a, 67.01 g,185.0 mmol) were added at room temperature and the reaction mixture wasdegassed with argon for 15 min. Bis(triphenylphosphine)palladium(II)chloride (8.6 g, 12.3 mmol) was added to the reaction, continueddegassing for 5 min and heated the reaction mixture at 100° C. for 16 h.After completion, the reaction mass was diluted with ethyl acetate (300mL) and washed with water. The organic layer was separated and driedover sodium sulphate, filtered and concentrated to give crude. The crudewas treated with 1N hydrochloric acid (100 mL) and the reaction mixturewas stirred at room temperature for 1 h. The mixture was then basifiedwith Sodium bicarbonate solution up to pH˜7 and extracted with ethylacetate (300 mL) and washed with water. The organic layer was separatedand dried over sodium sulphate, filtered and concentrated to give crude.The crude was purified by silica gel column chromatography eluting with10% ethyl acetate in hexane. The desired fractions were concentrated toafford 1-(4-amino-2-methoxypyridin-3-yl) ethan-1-one (3) as off whitesolid. Yield: 10.0 g, 65%; MS (ESI) m/z 167.16[M+]⁺.

Synthesis of 1-(4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (4)

To a solution of 1-(4-amino-2-methoxypyridin-3-yl)ethan-1-one (3, 10.0g, 59.8 mmol) in 1,4-dioxane (250 mL) at 0° C., 50% aq. sulfuric acidsolution (117.3 g, 1196.9 mmol) was added drop wise over a period of 30min. A solution of sodium nitrite in water (16.5 g, 239.5 mmol) wasadded drop wise at 0° C. and heated the reaction mixture at 50° C. for 1h. After completion, the reaction mass was quenched with 10% sodiumhydroxide solution to pH ˜7 and extracted with ethyl acetate (200 mL).The organic layer was separated and washed water, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Thecrude was purified by silica gel column chromatography eluting with 5%ethyl acetate in hexane. The desired fractions were concentrated toafford 1-(4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (4) as yellowsolid. Yield: 3.7 g, 37.2%; MS (ESI) m/z: no ionization

Synthesis of(E)-3-(4-bromophenyl)-1-(4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one(6)

To a solution of 1-(4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (4, 3.7g, 22.1 mmol) in methanol (40 mL), sodium hydroxide (2.6 g, 66.3 mmol)was added followed by addition of 4-bromobenzaldehyde (5, 4.0 g, 22.1mmol). The reaction was heated to reflux for 30 min. After completion,the reaction mass was cooled to room temperature and the mixture wasdiluted with water (20 mL). The precipitated solid was filtered, washedwith water, n-pentane and dried under vacuum to afford(E)-3-(4-bromophenyl)-1-(4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one(6) as yellow solid. Yield: 5.0 g, 68.0%; MS (ESI) m/z 334.10[M+1]⁺.

Synthesis of2-(4-bromophenyl)-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one (7)

To a solution of(E)-3-(4-bromophenyl)-1-(4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one(6, 6.0 g, 18.0 mmol) in ethanol (60 mL) and dichloromethane (10 mL) at0° C., 10% aq. sodium hydroxide (50 mL, 126.6 mmol) was added followedby addition of 30% aq. hydrogen peroxide (4.2 mL, 126.6 mmol). Thereaction mass was stirred for 30 min at room temperature (exotherm wasobserved). After completion, the reaction mass was cooled andneutralized to pH ˜7 by the addition of 6 M hydrogen chloride. Themixture was extracted with ethyl acetate (100 mL) and the organic layerwas washed with water and brine, dried over anhydrous sodium sulfate,filtered and concentrated. The solid obtained was triturated withn-pentane and ethanol, filtered and dried under vacuum to afford of2-(4-bromophenyl)-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one (7)as yellow solid. Yield: 2.0 g, 32.2%; MS (ESI) m/z 348.07 [M+1]⁺.

Synthesis of methyl5a-(4-bromophenyl)-7a-hydroxy-1-methoxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-c]pyridine-7-carboxylate(9)

A solution of2-(4-bromophenyl)-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one (7,2.0 g, 5.7 mmol) and methyl cinnamate (8, 9.34 g, 50.7 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedfor 8 h under 400 watts UV light. After completion, solvent was removedunder reduced pressure and the residue was purified over a plug ofsilica gel eluting the compound with ethyl acetate. The desiredfractions were concentrated under reduced pressure to afford methyl5a-(4-bromophenyl)-7a-hydroxy-1-methoxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-c]pyridine-7-carboxylate(9) as yellow sticky mass. Yield: 1.7 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-1-methoxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(10)

The crude methyl5a-(4-bromophenyl)-7a-hydroxy-1-methoxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-c]pyridine-7-carboxylate(9, 1.7 g, 3.3 mmol) was suspended in methanol (20 mL) and treated with25% sodium methoxide in methanol (15 mL). The reaction was heated at 80°C. for 2 h. After completion, the solvent was removed under reducedpressure. The crude was diluted with ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and concentrated under reduced pressure to affordrac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-1-methoxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(10). Yield: 1.6 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(11)

To a solution of sodium triacetoxyborohydride (3.99 g, 18.8 mmol),rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-1-methoxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(10, 1.6 g, 3.1 mmol) in acetonitrile (20 mL), acetic acid (1.77 g, 31.5mmol) was added. The resulting mixture was stirred for 12 h at roomtemperature. After completion, the reaction mixture was partitionedbetween saturated aqueous sodium bicarbonate solution and ethyl acetate.The organic layer was separated, dried over sodium sulphate, filteredand concentrated under reduced pressure to get the crude. The crude waspurified by prep HPLC purification and lyophilized to afford rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(11) as yellowish solid. Yield: 0.03 g, 2.0%; MS (ESI) m/z 512.1[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (12)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(11, 0.03 g, 0.06 mmol) in tetrahydrofuran and water (3:1, 4 mL),lithium hydroxide (0.015 g, 0.06 mmol) was added and the reaction wasstirred for 2 h at room temperature. After completion, the reaction masswas cooled to 0° C. and acidified with 1 M hydrochloric acid to pH ˜2-3.The precipitate was filtered and dried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (12) as yellow solid. Yield: 0.02 g, 69.3%; MS (ESI) m/z498.24[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(13)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (12, 0.02 g, 0.04 mmol) in dichloromethane (2 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.019 g, 0.12 mmol),hydroxybenzotriazole (0.018 g, 0.12 mmol) and N,N-diisopropylethylamine(0.04 g, 0.24 mmol) were added and the mixture was stirred for 5 min.Dimethylamine hydrochloride (0.016 g, 0.20 mmol) was then added at thesame temperature and the reaction was stirred for 16 h at roomtemperature. After completion, the reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by silica gel column chromatographyeluting with 2-3% dichloromethane in methanol. The desired fractionswere concentrated to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(13) as yellow sticky mass. Yield: 0.02 g, 95%; MS (ESI) m/z525.15[M+1]⁺;

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(Cpd. No. 19F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(13, 0.02 g, 0.04 mmol) in N,N-dimethylformamide (1.0 mL), zinc cyanide(0.026 g, 0.22 mmol) and zinc (0.001 g, 0.004 mmol) were added at roomtemperature and the reaction mixture was degassed with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.5 mg, 0.0001 mmol) andtris(dibenzylideneacetone) dipalladium (1.0 mg, 0.0001 mmol) were addedto the reaction, continued degassing for 5 min and heated the reactionmixture at 140° C. for 4 h. After completion, the reaction mass wasdiluted with ethyl acetate and washed with cold water. The organic layerwas separated and dried over sodium sulphate, filtered and concentratedto give crude. The crude was purified by prep HPLC and lyophilized toaffordrac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(Cpd. No. 19F) as white solid. Yield: 3.5 mg, 20%; MS (ESI) m/z472.44[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (d, J=5.6 Hz, 1H), 7.50(d, J=8.8 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.03 (t, J=8.0 Hz, 2H), 6.96(t, J=7.2 Hz, 1H), 6.90 (d, J=7.6 Hz, 2H), 6.83 (d, J=5.6 Hz, 1H), 5.61(s, 1H), 5.10 (bs, 1H), 4.75 (d, J=5.2 Hz, 1H), 4.44 (d, J=13.6 Hz, 1H),4.26 (dd, J=13.6, 5.2 Hz, 1H), 3.85 (s, 3H), 3.28 (s, 3H), 2.77 (s, 3H).

Example 20(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 20F)

Synthesis of(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamideCpd. No. 20F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (1, 0.13 g, 0.29 mmol) in dichloromethane (10 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.13 g,0.87 mmol), 1-hydroxybenzotriazole (0.12 g, 0.87 mmol) andN,N-diisopropylethylamine (0.5 mL, 2.9 mmol) were added at 0° C. andstirred the mixture for 5 min. Methylamine hydrochloride (0.097 g, 1.45mmol) was then added at same temperature and the mixture was stirred for16 h at 40° C. After completion, reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentratedunder reduced pressure to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(rac-Cpd. No. 20F) as brown solid. Yield: 120 mg, 90%. The enantiomerswere separated by chiral preparative HPLC [chiralpak IC (4.6×250) mm].Peak 1 (22 mg); [α]_(D) +51.4° (c 0.14, CHCl₃); R_(t)=5.66 min, ee>99%;MS (ESI) m/z 462.41[M+1]⁺; UPLC: 99.09%; ¹H NMR (400 MHz, DMSO-d₆) δ8.20 (d, J=2.0 Hz, 1H), 8.17 (q, J=4.3 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H),7.51 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 7.08-6.96 (m, 5H), 6.19(s, 1H), 5.29 (d, J=4.5 Hz, 1H), 4.61 (d, J=14.0 Hz, 1H), 4.52 (t, J=4.4Hz, 1H), 3.95 (dd, J=14.0, 4.4 Hz, 1H), 2.55 (d, J=4.5 Hz, 3H). Peak-2(Cpd. No. 20F, 18 mg); [α]_(D) −178° (c 0.13, CHCl₃); R_(t)=7.24 min,ee>99%; MS (ESI) m/z 462.42[M+1]⁺; UPLC: 99.61%; ¹H NMR (400 MHz,DMSO-d₆) δ 8.20 (d, J=2.0 Hz, 1H), 8.17 (q, J=4.3 Hz, 1H), 7.71 (d,J=1.9 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 7.08-6.96(m, 5H), 6.19 (s, 1H), 5.29 (d, J=4.5 Hz, 1H), 4.61 (d, J=14.0 Hz, 1H),4.52 (t, J=4.4 Hz, 1H), 3.96 (dd, J=14.0, 4.4 Hz, 1H), 2.56 (d, J=4.6Hz, 3H).

Example 21 Rac-methyl(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-2-methyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(Cpd. No. 21F)

Synthesis of rac-methyl(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-2-methyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(Cpd. No. 21F)

To a solution of rac-methyl(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-methyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(1, 0.018 g, 0.037 mmol) in N,N-dimethylformamide (1.0 mL), zinc cyanide(0.026 g, 0.22 mmol) and zinc (0.001 g, 0.004 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.001 g, 0.0007 mmol),tris(dibenzylideneacetone)dipalladium (0.002 g, 0.0009 mmol) were addedto the reaction and degassing was continued for another 5 min. Thereaction mixture was heated at 140° C. for 2 h. After completion, thereaction mass was diluted with ethyl acetate and washed with cold water.The organic layer was separated and dried over sodium sulphate, filteredand concentrated to give crude. The crude was purified by silica gelcolumn chromatography using 2-3% methanol in dichloromethane as eluent.The desired fractions were concentrated to afford rac-(4aR,5S,6R,7R,7aS)-3-chloro-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 21F) as white solid. Yield: 0.004 g, 25%; (racemic mixture).¹H NMR (400 MHz, DMSO-d₆) δ 7.49 (d, J=8.4 Hz, 2H), 7.32 (s, 1H), 7.27(d, J=8.4 Hz, 2H), 7.07-6.98 (m, 3H), 6.87 (d, J=7.2 Hz, 2H), 5.77 (s,1H), 5.71 (brs, 1H), 4.66 (d, J=4.8 Hz, 1H), 4.35 (d, J=14.0 Hz, 1H),4.05 (dd, J=14.0, 6.0 Hz, 1H), 3.79 (s, 3H), 3.54 (s, 3H); MS (ESI) m/z432.4[M+1]⁺.

Example 22Rac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(Cpd. No. 22F)

Synthesis ofrac-5a-(4-bromophenyl)-3-chloro-7a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-sulfonamide(3/3a)

A solution of2-(4-bromophenyl)-7-chloro-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one (1,1.5 g, 4.27 mmol) and (E)-N,N-dimethyl-2-phenylethene-1-sulfonamide (2,4.50 g, 21.4 mmol) in dichloromethane (200 mL), acetonitrile (100 mL)and methanol (100 mL) was placed in a UV reactor flask. The reactionmixture was irradiated for 3 day under 400 watts UV light. Aftercompletion, the solvent was removed under reduced pressure. The crudewas purified by Combi-flash (4 g, RediSep column) using ethyl acetate aseluent. The desired fractions were concentrated under reduced pressureto affordrac-5a-(4-bromophenyl)-3-chloro-7a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-sulfonamide(3/3a) as brown solid. Yield: 0.7 g, Crude.

Synthesis ofrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(4)

The cruderac-5a-(4-bromophenyl)-3-chloro-7a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-sulfonamide(3, 0.7 g) was suspended in methanol (20 mL) and treated with sodiummethoxide (25% in methanol, 10 mL) and heated the mixture to 80° C. for2 h. After completion, the solvent was removed under reduced pressureand the reaction was treated with ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and concentrated under reduced pressure to affordrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(4) as brown solid. Yield: 0.35 g, crude

Synthesis ofrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(5)

To a solution of sodium triacetoxyborohydride (1.27 g, 3.73 mmol) andrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(4, 0.35 g, 0.622 mmol) in acetonitrile (20 mL), acetic acid (4.0 mL,6.22 mmol) was added. The resulting mixture was stirred for 15 h at roomtemperature. After completion, reaction mixture was partitioned betweensaturated aqueous sodium bicarbonate solution and ethyl acetate. Theorganic layer was separated, dried over sodium sulphate and concentratedunder reduced pressure to get the crude. The crude was purified byCombi-flash (4 g, RediSep column) using 50% ethyl acetate in hexanes aseluent. The obtained compound was purified by reverse phase HPLC. Thedesired fractions were concentrated under reduced pressure to affordrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(5) as light yellow solid. Yield: 0.04 g, 10%. MS (ESI) m/z565.06[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(Cpd. No. 22F)

To a solution ofrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(0.03 g, 0.053 mmol) in N,N-dimethylformamide, zinc cyanide (0.005 g,0.063 mmol) and zinc (0.001 g, 0.0053 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.001 g, 0.001 mmol),tris(dibenzylideneacetone)dipalladium (0.002 g, 0.002 mmol) were addedto the reaction and degassing was continued for 5 min. The reactionmixture was heated at 140° C. for 1 h. After completion, the reactionwas cooled to room temperature and passed through celite bed. Thefiltrate was purified by Combi-flash (4 g, RediSep column) using 10%methanol in dichloromethane as eluent. Finally the compound was purifiedthrough reverse phase HPLC. The desired fractions were concentratedunder reduced pressure to affordrac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(Cpd. No. 22F) as off white solid. Yield: 0.002 g, 7.3%; MS (ESI) m/z512.45[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (d, J=1.9 Hz, 1H), 7.69(d, J=1.9 Hz, 1H), 7.49 (dd, J=14.6 Hz, 8.9 Hz, 4H), 7.14 (d, J=7.2 Hz,2H), 7.08-6.99 (m, 3H), 6.44 (s, 1H), 5.97 (d, J=6.2 Hz, 1H), 4.95 (dd,J=13.8, 4.0 Hz, 1H), 4.65 (t, J=6.0 Hz, 1H), 4.58 (d, J=13.6, Hz, 1H),2.46 (s, 6H).

Example 23(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 23F)

Synthesis of (E)-1-(2-methylhydrazono)propan-2-one (2)

To a solution of 2-oxopropanal (1, 56.0 g, 777.3 mmol, 35% aqueoussolution) in acetic acid (100 mL), methylhydrazine (36.0 g, 777.3 mmol,80% aqueous solution) was added at 0° C. The reaction was stirred atroom temperature for 16 h and then heated at 100° C. for 6 h. Aftercompletion, reaction mixture was diluted with ethyl acetate and washedwith cold water. The organic layer was separated and dried over sodiumsulphate, filtered and concentrated under reduced pressure to givecrude. The crude was purified by silica gel column chromatography using20% ethyl acetate in hexanes as eluent. The desired fractions wereconcentrated to afford (E)-1-(2-methylhydrazono)propan-2-one (2) asbrown solid. Yield: 13.0 g, 16.8%; MS (ESI) m/z 101.02[M+1]⁺.

Synthesis of 1-(4-hydroxy-1-methyl-1H-pyrazol-3-yl)ethan-1-one (3)

To glyoxal (38.0 mL, 260.0 mmol, 40% aqueous solution),(E)-1-(2-methylhydrazono)propan-2-one (2, 13.0 g, 130.0 mmol) was addedand the mixture was stirred at 110° C. for 2 h. After completion,reaction mixture was diluted with ethyl acetate and washed with coldwater. The organic layer was separated and dried over sodium sulphate,filtered and concentrated to give crude. The crude was purified bysilica gel column chromatography using 30% ethyl acetate in hexanes aseluent. The desired fractions were concentrated to afford1-(4-hydroxy-1-methyl-1H-pyrazol-3-yl)ethan-1-one (3) as brown solid.Yield: 12.0 g, 65.9%; MS (ESI) m/z 141.04[M+1]⁺.

Synthesis of(E)-3-(4-bromophenyl)-1-(4-hydroxy-1-methyl-1H-pyrazol-3-yl)prop-2-en-1-one(4)

To a solution of 1-(4-hydroxy-1-methyl-1H-pyrazol-3-yl)ethan-1-one (3,12.0 g, 85.7 mmol) in methanol (70 mL), sodium hydroxide (10.28 g, 257.1mmol) was added followed by addition of 4-bromobenzaldehyde (15.77 g,85.7 mmol) and the reaction mixture was heated at 90° C. for 30 min.After completion, reaction mass was cooled to room temperature and theprecipitated solid was filtered, washed with water and dried undervacuum to afford of(E)-3-(4-bromophenyl)-1-(4-hydroxy-1-methyl-1H-pyrazol-3-yl)prop-2-en-1-one(4) as yellow solid. Yield: 24.5 g, 98%; MS (ESI) m/z 307 [M+1]+.

Synthesis of5-(4-bromophenyl)-6-hydroxy-2-methylpyrano[3,2-c]pyrazol-7(2H)-one (5)

To a solution of(E)-3-(4-bromophenyl)-1-(4-hydroxy-1-methyl-1H-pyrazol-3-yl)prop-2-en-1-one(4, 24.0 g, 78.4 mmol) in ethanol (240 mL) and dichloromethane (100 mL),10% aqueous sodium hydroxide solution (219 mL, 549.0 mmol) was addedfollowed by addition of hydrogen peroxide (62.57 mL, 549.0 mmol, 30%) atroom temperature. The reaction mass was stirred for 1 h (exotherm wasobserved). After completion, reaction mass was cooled and neutralizedwith 6 M hydrogen chloride to pH ˜7. The precipitated solid was filteredand dried under vacuum to afford5-(4-bromophenyl)-6-hydroxy-2-methylpyrano[3,2-c]pyrazol-7(2H)-one (5)as brown solid. Yield: 11.1 g, 44.4%; MS (ESI) m/z 319.09[M−1]⁻.

Synthesis of rac-methyl(6S,7S,8R)-5-(4-bromophenyl)-8-hydroxy-2-methyl-9-oxo-6-phenyl-5,6,7,8-tetrahydro-2H-5,8-methanooxepino[3,2-c]pyrazole-7-carboxylate(7)

A solution of5-(4-bromophenyl)-6-hydroxy-2-methylpyrano[3,2-c]pyrazol-7(2H)-one (5,11.0 g, 34.3 mmol) and methyl cinnamate (6, 55.6 g, 34.3 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedfor 8 h under 400 watts UV light. After completion, the solvent wasremoved under reduced pressure and the residue was purified over a plugof silica gel eluting the compound with 5% methanol in dichloromethane.The desired fractions were concentrated under reduced pressure to affordrac-methyl(6S,7S,8R)-5-(4-bromophenyl)-8-hydroxy-2-methyl-9-oxo-6-phenyl-5,6,7,8-tetrahydro-2H-5,8-methanooxepino[3,2-c]pyrazole-7-carboxylate(7). Yield: 18.1 g, crude.

Synthesis of rac-methyl(4aR,5S,6R,7aR)-4a-(4-bromophenyl)-7a-hydroxy-2-methyl-7-oxo-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(8)

The crude rac-methyl(6S,7S,8R)-5-(4-bromophenyl)-8-hydroxy-2-methyl-9-oxo-6-phenyl-5,6,7,8-tetrahydro-2H-5,8-methanooxepino[3,2-c]pyrazole-7-carboxylate(7, 18.0 g) was suspended in methanol (100 mL) and treated with sodiummethoxide (25% in methanol, 90 mL) and heated the mixture to 90° C. for3 h. After completion, the solvent was removed under reduced pressure,diluted the mixture with ammonium chloride solution and extracted withethyl acetate. The organic phase was separated, dried over sodiumsulphate and concentrated under reduced pressure to afford rac-methyl(4aR,5S,6R,7aR)-4a-(4-bromophenyl)-7a-hydroxy-2-methyl-7-oxo-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(8). Yield: 14.0 g, crude.

Synthesis of rac-methyl(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-methyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(9)

To a solution of sodium triacetoxyborohydride (18.4 g, 87.1 mmol),rac-methyl(4aR,5S,6R,7aR)-4a-(4-bromophenyl)-7a-hydroxy-2-methyl-7-oxo-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(8, 7.0 g) in acetonitrile (100 mL), acetic acid (9 mL, 145.0 mmol) wasadded. The resulting mixture was stirred for 18 h at room temperature.After completion, reaction mixture was partitioned between saturatedaqueous sodium bicarbonate solution and ethyl acetate. The organic layerwas separated, dried over sodium sulphate and concentrated under reducedpressure to get the crude. The crude was purified by silica gel columnchromatography using 80% ethyl acetate in hexanes as eluent. The desiredfractions were concentrated to afford rac-methyl(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-methyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(9) as off white solid. Yield: 1.4 g, 20.0%; MS (ESI) m/z 485.06[M+1]⁺.

Synthesis ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-methyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylicacid (10)

To a solution of rac-methyl(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-methyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(9, 1.3 g, 2.68 mmol) in methanol: tetrahydrofuran: water (3:2:1, 18mL), lithium hydroxide (1.12 g, 23.0 mmol) was added and the reactionwas stirred for 3 h at room temperature. After completion, the reactionmass was cooled to 0° C. and acidified with 1 M hydrogen chloride to pH˜3. The precipitated solid was filtered and dried under vacuum to affordrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-methyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylicacid (10) as white solid. Yield: 1.21 g, 95.4%; MS (ESI) m/z471.19[M+1]⁺.

Synthesis ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide (11)

To a solution ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(10, 1.2 g, 2.55 mmol) in dichloromethane (30 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.18 g,7.65 mmol), 1-hydroxybenzotriazole (1.17 g, 7.65 mmol) andN,N-diisopropylethylamine (2.45 mL, 15.3 mmol) were added at 0° C. andstirred the mixture for 5 min. Dimethylamine hydrochloride (1.04 g, 12.7mmol) was then added at same temperature and the mixture was stirred for16 h at 40° C. After completion, reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by silica gel column chromatographyusing 3% methanol in dichloromethane as eluent. The desired fractionswere concentrated to affordrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(11) as white solid. Yield: 1.0 g, 78.7%; MS (ESI) m/z 498.09[M+1]⁺.

Synthesis of(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 23F)

To a solution ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(11, 0.5 g, 1.0 mmol) in N,N-dimethylformamide (10.0 mL), zinc cyanide(0.71 g, 6.0 mmol) and zinc (0.008 g, 0.12 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.011 g, 0.012 mmol),tris(dibenzylideneacetone)dipalladium (0.027 g, 0.03 mmol) were added tothe reaction and degassing was continued for another 5 min. The reactionmixture was heated at 140° C. for 3 h. After completion, the reactionmass was diluted with ethyl acetate and washed with cold water. Theorganic layer was separated and dried over sodium sulphate, filtered andconcentrated to give crude. The crude was purified by silica gel columnchromatography using 2-3% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to afford rac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(rac-Cpd. No. 23F) as white solid. The enantiomers were separated bychiral preparative HPLC [chiralpak IB (4.6×250) mm]. Yield: 0.26 g,(racemic mixture). Peak 1 (Cpd. No. 23F, 100 mg), [α]_(D) −100.5° (c0.1, CHCl₃), R_(t)=4.419 min, ee>99%. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.53(d, J=8.8 Hz, 2H), 7.35 (s, 1H), 7.32 (d, J=8.4 Hz, 2H), 7.03-6.94 (m,3H), 6.80 (d, J=6.8 Hz, 2H), 5.64 (s, 1H), 5.21 (d, J=6.2 Hz, 1H), 4.81(t, J=6.8 Hz, 1H), 4.42 (d, J=13.4 Hz, 1H), 4.07 (dd, J=13.4, 7.6 Hz,1H), 3.81 (s, 3H), 3.20 (s, 3H), 2.73 (s, 3H); MS (ESI) m/z 445.5[M+1]⁺.Peak-2 (95 mg), [α]_(D) +95.5° (c 0.1, CHCl₃), R_(t)=7.878 min, ee>99%.¹H NMR (400 MHz, DMSO-d₆) δ: 7.53 (d, J=8.6 Hz, 2H), 7.35 (s, 1H), 7.32(d, J=8.4 Hz, 2H), 6.99 (m, 3H), 6.80 (d, J=7.0 Hz, 2H), 5.64 (s, 1H),5.21 (d, J=6.28 Hz, 1H), 4.81 (t, J=7.0 Hz, 1H), 4.42 (d, J=13.2 Hz,1H), 4.07 (dd, J=13.3, 7.6 Hz, 1H), 3.81 (s, 3H), 3.20 (s, 3H), 2.73 (s,3H); MS (ESI) m/z 445.5[M+1]⁺.

Example 24 Rac-methyl(5aR,6R,6aS,7aS,7bR)-3-chloro-5a-(4-cyanophenyl)-7b-hydroxy-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxylate(Cpd. No. 24F)

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-((methylsulfonyl)oxy)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(1, 1.3 g, 2.5 mmol) in pyridine (5 mL) under nitrogen, methanesulphonylchloride (0.3 mL, 3.7 mmol) was added at room temperature. The reactionmixture was stirred at room temperature for 6 h. After completion, thereaction mixture was diluted with ethyl acetate (50 mL) and washed withwater (20 mL) and brine (20 mL). The organic layer was dried overanhydrous sodium sulphate and concentrated under reduced pressure to getcrude. The crude was triturated with n-pentane and diethyl-ether. Theprecipitated solid was filtered and dried under vacuum to affordrac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-((methylsulfonyl)oxy)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2) as yellow solid. Yield: 1.4 g, 93.5%; MS (ESI) m/z 594.18[M+1]⁺.

Synthesis of rac-methyl(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,8a-dihydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate (3)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-((methylsulfonyl)oxy)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2, 1.3 g, 2.18 mmol) in chloroform (10 mL), triethylamine (5 mL) wasadded at room temperature. The reaction mixture was stirred at 85° C.for 16 h. After completion of reaction, water (50 mL) was added and thenextracted with ethyl acetate (60 mL). The organic layer was washed withbrine and dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to get the crude. The crude waspurified by Combi-flash (4 g, RediSep column) using 30% ethyl acetate inhexanes as eluent. The desired fractions were concentrated to affordrac-methyl(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,8a-dihydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(3) as white solid. Yield: 0.65 g, 60%; MS (ESI) m/z 498.18[M+1]⁺.

Synthesis of rac-methyl(5aR,6R,6aS,7aS,7bR)-5a-(4-bromophenyl)-3-chloro-7b-hydroxy-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxylate(Cpd. No. 24F)

To a solution of sodium hydride (72 mg, 1.8 mmol) in dimethyl sulfoxide(15 mL) under nitrogen, trimethylsulfoxonium iodide (0.42 g, 1.92 mmol)was added at room temperature and allowed to stir at room temperaturefor 1 h. Then rac-methyl(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,8a-dihydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(600 mg, 1.2 mmol) in dimethyl sulfoxide: tetrahydrofuran (1:1) wasadded to above suspension at 0° C. and the reaction mixture was stirredat room temperature for 16 h. After completion, water (30 mL) was addedand then extracted with ethyl acetate (50 mL). The organic layer waswashed with brine and dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to get the crude. The crudecontaining starting material and desired product at same retentionfactor (R_(f)) on TLC and LCMS, was purified by reverse phase HPLC. Thedesired fractions were concentrated to afford rac-methyl(5aR,6R,6aS,7aS,7bR)-5a-(4-bromophenyl)-3-chloro-7b-hydroxy-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxylate(Cpd. No. 24F) as white solid. Yield: 58 mg, 10%; MS (ESI) m/z512.34[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (s, 1H), 7.79 (s, 1H),7.26 (d, J=8.2 Hz, 2H), 7.18-7.11 (m, 5H), 7.02 (d, J=8.24 Hz, 2H), 6.18(s, 1H), 4.53 (s, 1H), 3.48 (s, 3H), 2.58 (d, J=5.0 Hz, 1H), 1.94 (t,J=8 Hz, 1H), 1.87 (t, J=3.76 Hz, 1H).

Example 25 Rac-methyl(5aR,6R,6aS,7aS,7bR)-3-chloro-5a-(4-cyanophenyl)-7b-hydroxy-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxylate(Cpd. No. 25F)

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-((methylsulfonyl)oxy)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(1, 1.3 g, 2.5 mmol) in pyridine (5 mL) under nitrogen, methanesulphonylchloride (0.3 mL, 3.7 mmol) was added at room temperature. The reactionmixture was stirred at room temperature for 6 h. After completion, thereaction mixture was diluted with ethyl acetate (50 mL) and washed withwater (20 mL) and brine (20 mL). The organic layer was dried overanhydrous sodium sulphate and concentrated under reduced pressure to getcrude. The crude was triturated with n-pentane and diethyl-ether. Theprecipitated solid was filtered and dried under vacuum to affordrac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-((methylsulfonyl)oxy)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2) as yellow solid. Yield: 1.4 g, 93.5%; MS (ESI) m/z 594.18[M+1]⁺.

Synthesis of rac-methyl(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,8a-dihydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate (3)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-((methylsulfonyl)oxy)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2, 1.3 g, 2.18 mmol) in chloroform (10 mL), triethylamine (5 mL) wasadded at room temperature. The reaction mixture was stirred at 85° C.for 16 h. After completion of reaction, water (50 mL) was added and thenextracted with ethyl acetate (60 mL). The organic layer was washed withbrine and dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to get the crude. The crude waspurified by Combi-flash (4 g, RediSep column) using 30% ethyl acetate inhexanes as eluent. The desired fractions were concentrated to affordrac-methyl(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,8a-dihydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(3) as white solid. Yield: 0.65 g, 60%; MS (ESI) m/z 498.18[M+1]⁺.

Synthesis of rac-methyl(5aR,6R,6aS,7aS,7bR)-5a-(4-bromophenyl)-3-chloro-7b-hydroxy-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxylate(4)

To a solution of sodium hydride (72 mg, 1.8 mmol) in dimethyl sulfoxide(15 mL) under nitrogen, trimethylsulfoxonium iodide (0.42 g, 1.92 mmol)was added at room temperature and allowed to stir at room temperaturefor 1 h. Then rac-methyl(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,8a-dihydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(600 mg, 1.2 mmol) in dimethyl sulfoxide: tetrahydrofuran (1:1) wasadded to above suspension at 0° C. and the reaction mixture was stirredat room temperature for 16 h. After completion, water (30 mL) was addedand then extracted with ethyl acetate (50 mL). The organic layer waswashed with brine and dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to get the crude. The crudecontaining starting material and desired product at same retentionfactor (Rj) on TLC and LCMS, was purified by reverse phase HPLC. Thedesired fractions were concentrated to afford rac-methyl(5aR,6R,6aS,7aS,7bR)-5a-(4-bromophenyl)-3-chloro-7b-hydroxy-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxylate(4) as white solid. Yield: 58 mg, 10%; MS (ESI) m/z 512.34[M+1]⁺; UPLC:99.85%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (s, 1H), 7.79 (s, 1H), 7.26 (d,J=8.2 Hz, 2H), 7.18-7.11 (m, 5H), 7.02 (d, J=8.24 Hz, 2H), 6.18 (s, 1H),4.53 (s, 1H), 3.48 (s, 3H), 2.58 (d, J=5.0 Hz, 1H), 1.94 (t, J=8 Hz,1H), 1.87 (t, J=3.76 Hz, 1H).

Synthesis of rac-methyl(5aR,6R,6aS,7aS,7bR)-3-chloro-5a-(4-cyanophenyl)-7b-hydroxy-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxylate(Cpd. No. 25F)

To a solution of rac-methyl(5aR,6R,6aS,7aS,7bR)-5a-(4-bromophenyl)-3-chloro-7b-hydroxy-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxylate(4, 20 mg, 0.039 mmol) in N,N-dimethylformamide (10.0 mL), zinc cyanide(10 mg, 0.156 mmol) and zinc (9 mg, 0.078 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (1.0 mg, 0.018 mmol),tris(dibenzylideneacetone) dipalladium (1.0 mg, 0.00078 mmol) were addedto the reaction and degassing was continued for another 5 min. Thereaction mixture was heated at 130° C. for 6 h. After completion, thereaction was cooled to room temperature and passed through celite bed.The filtrate was diluted with ethyl acetate and washed with water. Theorganic layer was separated, dried over sodium sulphate and concentratedunder reduced pressure to get the crude containing desired product anddicyano (side product). The crude was purified by reverse phase HPLC.The desired fractions were concentrated under reduced pressure to affordrac-methyl(5aR,6R,6aS,7aS,7bR)-3-chloro-5a-(4-cyanophenyl)-7b-hydroxy-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxylate(Cpd. No. 25F) as white solid. Yield: 3 mg, 15.7%; MS (ESI) m/z459.40[M+1]⁺; UPLC: 97.51%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (d, J=1.9Hz, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.27 (d, J=8.5Hz, 2H), 7.19-7.09 (m, 5H), 6.28 (s, 1H), 4.59 (s, 1H), 3.48 (s, 3H),3.17 (d, J=5.2 Hz, 1H), 1.98 (t, J=5.5 Hz, 1H), 1.90 (t, J=8.7 Hz, 1H).

Example 26Rac-4-((5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-7-(oxazol-2-yl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 26F)

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-N-(2,2-diethoxyethyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(3)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (1, 1.4 g, 2.7 mmol) in dichloromethane (20 mL),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.6 g, 8.3mmol), 1-hydroxybenzotriazole (1.13 g, 8.3 mmol) andN,N-diisopropylethylamine (2.88 mL, 16.0 mmol) were added at 0° C. andstirred the mixture for 5 min. 2,2-diethoxyethan-1-amine (2, 2.35 g,13.0 mmol) was then added at same temperature and the reaction wasstirred at 35° C. for 16 h. After completion, reaction mass was dilutedwith dichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by Combi-flash (12 g,RediSep column) using 2% methanol in dichloromethane as eluent. Thedesired fractions were concentrated under reduced pressure to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-N-(2,2-diethoxyethyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(3) as light brown oil. Yield: 1.1 g, 64%; MS (ESI) m/z 617.12[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N-(2-oxoethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(4)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-N-(2,2-diethoxyethyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(3, 1.0 g, 1.6 mmol) in tetrahydrofuran (5.0 mL), 2N hydrochloric acid(5.0 mL) was added. The reaction mixture was stirred for 4 h at roomtemperature. After completion, the reaction mass diluted with ethylacetate and organic layer was separated and dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N-(2-oxoethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(4) as white solid. Yield: 0.91 g, crude, MS (ESI) m/z 543.23[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(oxazol-2-yl)-6-phenyl-5a,6,7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (5)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N-(2-oxoethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(4, 0.9 g, 1.6 mmol) in dichloromethane (20.0 mL), triphenyl phosphine(0.87 g, 3.0 mmol), iodine (0.83 g, 3.3 mmol) and triethylamine (0.86mL, 6.4 mmol) were added. The reaction mixture was stirred at roomtemperature for 16 h. After completion, the reaction mass diluted withdichloromethane and organic layer was washed with water (2×20 mL) andbrine (20 mL). The organics layer was separated and dried over anhydroussodium sulphate before concentration to dryness. The crude was purifiedby Combi-flash (4 g, RediSep column) using 2% methanol indichloromethane as eluent. The desired fractions were concentrated toaffordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(oxazol-2-yl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(5) as off white solid. Yield: 0.18 g, 20%, MS (ESI) m/z 525.15[M+1]⁺.

Synthesis ofrac-4-((5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-7-(oxazol-2-yl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 26F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(oxazol-2-yl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(5, 0.06 g, 0.095 mmol) in N,N-dimethylformamide (1.0 mL), zinc cyanide(0.012 g, 0.1 mmol) and zinc (0.014 g, 0.19 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.0013 g, 0.0019 mmol),tris(dibenzylideneacetone)dipalladium (0.0026 g, 0.0028 mmol) were addedto the reaction and degassing was continued for another 5 min. Thereaction mixture was heated at 150° C. for 2 h. After completion, thereaction was cooled to room temperature and passed through celite bed.The filtrate was diluted with ethyl acetate and washed with water. Theorganic layer was separated, dried over sodium sulphate and concentratedunder reduced pressure to get the crude. The crude was purified byCombi-flash (4 g, RediSep column) using 2% methanol in dichloromethaneas eluent. The desired fractions were concentrated under reducedpressure. The compound obtained was further given for reverse phaseHPLC. The desired fractions were collected and were lyophilized toaffordrac-4-((5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-7-(oxazol-2-yl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 26F) as white solid. Yield: 0.012 g, 27%; MS (ESI) m/z472.40[M+1]⁺. UPLC: 99.63%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (d, J=2.0Hz, 1H), 7.94 (s, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.49 (d, J=8.5 Hz, 2H),7.35 (d, J=8.5 Hz, 2H), 7.04-6.94 (m, 6H), 6.36 (brs, 1H), 5.60 (brs,J=5.0 Hz, 1H), 4.85 (d, J=14.0 Hz, 1H), 4.68 (dd, J=14.0, 4.2 Hz, 1H),4.60 (d, J=4.1 Hz, 1H).

Example 27Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbothioamide(Cpd. No. 27F)

Synthesis ofrac-5a-(4-bromophenyl)-3-chloro-7a-hydroxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carbonitrile (3/3a)

A solution of2-(4-bromophenyl)-7-chloro-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one (1,5.0 g, 14.25 mmol) and cinnamonitrile (2, 18.3 g, 142.4 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedfor 16 h under 400 watts UV light. After completion, the solvent wasremoved under reduced pressure and the residue was purified byCombi-flash (24 g RediSep column) using ethyl acetate as eluent. Thedesired fractions were concentrated under reduced pressure to affordrac-5a-(4-bromophenyl)-3-chloro-7a-hydroxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carbonitrile(3/3a) as brown solid. Yield: 6.0 g; crude.

Synthesis ofrac-(5aR,6S,7S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbonitrile(4)

The cruderac-5a-(4-bromophenyl)-3-chloro-7a-hydroxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carbonitrile(3, 6.0 g) was suspended in methanol (60 mL) and treated with sodiummethoxide (25% in methanol, 60 mL) and heated the mixture to 70° C. for1 h. After completion, the solvent was removed under reduced pressureand the reaction was quenched with ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and concentrated under reduced pressure to affordrac-(5aR,6S,7S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbonitrile(4) as brown solid. Yield: 6.0 g, crude.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbonitrile(Cpd. No. 27F)

To a solution of sodium triacetoxyborohydride (7.95 g, 37.5 mmol) andrac-(5aR,6S,7S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbonitrilecarboxylate (4, 6.0 g) in acetonitrile (70 mL), acetic acid (7.5 mL, 125mmol) was added. The resulting mixture was stirred at room temperaturefor 16 h. After completion, reaction mixture was partitioned betweensaturated aqueous sodium bicarbonate solution and ethyl acetate. Theorganic layer was separated, dried over sodium sulphate and concentratedunder reduced pressure to get the crude. The crude was purified byreverse phase HPLC. The desired fractions were concentrated underreduced pressure to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbonitrile(Cpd. No. 27F) as light yellow solid. Yield: 4.6 g, 76.0%; MS (ESI) m/z483.35[M+1]⁺. UPLC 97.0%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (d, J=1.9 Hz,1H), 7.72 (d, J=1.9 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H), 7.18-7.14 (m, 4H),7.12-7.06 (m, 3H), 6.43 (d, J=6.2 Hz, 1H), 6.29 (s, 1H), 4.58 (t, J=3.5Hz, 1H), 4.49 (dd, J=14.0, 4.0 Hz, 1H), 4.39 (d, J=14.0 Hz, 1H).

Example 28Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbothioamide(Cpd. No. 28F)

Synthesis ofrac-5a-(4-bromophenyl)-3-chloro-7a-hydroxy-8-oxo-6-phenyl-5a, 6, 7a,8-tetrahydro-7H-cyclobuta[5, 6]pyrano[3,2-b]pyridine-7-carbonitrile(3/3a)

A solution of2-(4-bromophenyl)-7-chloro-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one (1,5.0 g, 14.25 mmol) and cinnamonitrile (2, 18.3 g, 142.4 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedfor 16 h under 400 watts UV light. After completion, the solvent wasremoved under reduced pressure and the residue was purified byCombi-flash (24 g RediSep column) using ethyl acetate as eluent. Thedesired fractions were concentrated under reduced pressure to affordrac-5a-(4-bromophenyl)-3-chloro-7a-hydroxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carbonitrile(3/3a) as brown solid. Yield: 6.0 g; crude.

Synthesis ofrac-(5aR,6S,7S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbonitrile(4)

The cruderac-5a-(4-bromophenyl)-3-chloro-7a-hydroxy-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-carbonitrile(3, 6.0 g) was suspended in methanol (60 mL) and treated with sodiummethoxide (25% in methanol, 60 mL) and heated the mixture to 70° C. for1 h. After completion, the solvent was removed under reduced pressureand the reaction was quenched with ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and concentrated under reduced pressure to affordrac-(5aR,6S,7S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbonitrile(4) as brown solid. Yield: 6.0 g, crude.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbonitrile(5)

To a solution of sodium triacetoxyborohydride (7.95 g, 37.5 mmol) andrac-(5aR,6S,7S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbonitrile(4, 6.0 g) in acetonitrile (70 mL), acetic acid (7.5 mL, 125 mmol) wasadded. The resulting mixture was stirred at room temperature for 16 h.After completion, reaction mixture was partitioned between saturatedaqueous sodium bicarbonate solution and ethyl acetate. The organic layerwas separated, dried over sodium sulphate and concentrated under reducedpressure to get the crude. The crude was purified by reverse phase HPLC.The desired fractions were concentrated under reduced pressure to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbonitrile(5) as light yellow solid. Yield: 4.6 g, 76.0%; MS (ESI) m/z483.35[M+1]⁺. UPLC 97.0%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (d, J=1.9 Hz,1H), 7.72 (d, J=1.9 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H), 7.18-7.14 (m, 4H),7.12-7.06 (m, 3H), 6.43 (d, J=6.2 Hz, 1H), 6.29 (s, 1H), 4.58 (t, J=3.5Hz, 1H), 4.49 (dd, J=14.0, 4.0 Hz, 1H), 4.39 (d, J=14.0 Hz, 1H).

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbothioamide(Cpd. No. 28F)

A flask containing pyridine (3 mL) was charged withrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbonitrile(5, 0.5 g, 1.03 mmol) and triethylamine (0.15 mL,1.14 mmol) was added atroom temperature. The mixture was cooled to 0° C. and ammonium sulphide(40-48% by wt solution in water) (0.2 mL, 1.14 mmol) was added andstirred for 5 min. The reaction mixture was heated at 50° C. for 7 h.After completion, reaction mass was diluted with dichloromethane andwashed with 1 M hydrogen chloride. The organic layer was dried oversodium sulphate, filtered and concentrated to give crude. The crude waspurified by Combi-flash (4 g, RediSep column) using 70-90% ethyl acetatein hexanes as eluent. The desired fraction were concentrated to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbothioamide(Cpd. No. 28F) as white solid. Yield: 76 mg, 14.2%; MS (ESI) m/z517.31[M+1]⁺; UPLC 97.3%; ¹H NMR (400 MHz, DMSO-d₆) δ 9.67 (s, 1H), 9.21(s, 1H), 8.19 (d, J=1.9 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.21 (d, J=8.6Hz, 2H), 7.09-6.99 (m, 7H), 6.20 (brs, 1H), 5.56 (brs, 1H), 4.79 (d,J=14.3 Hz, 1H), 4.48 (d, J=3.9 Hz, 1H), 4.37 (dd, J=14.2, 3.9 Hz, 1H).

Example 29Rac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-3,8,8a-trihydroxy-N,N-dimethyl-6-phenyl-2-(trifluoromethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 29F)

Synthesis of(E)-1-(5-(benzyloxy)-3-hydroxypyridin-2-yl)-3-(4-bromophenyl)prop-2-en-1-one(3)

To a solution of 1-(5-(benzyloxy)-3-hydroxypyridin-2-yl)ethan-1-one (1,7.80 g, 32.06 mmol) and 4-bromobenzaldehyde (2, 5.83 g, 32.06 mmol) inmethanol (40 mL), sodium hydroxide (3.84 g, 96.18 mmol) was added. Thereaction was heated to reflux for 30 min. After completion, the reactionmass was cooled to room temperature and diluted with water (50 mL). Theprecipitated solid was filtered, washed with water, n-pentane and driedunder vacuum to afford(E)-1-(5-(benzyloxy)-3-hydroxypyridin-2-yl)-3-(4-bromophenyl)prop-2-en-1-one(3) as yellow solid. Yield: 12.0 g, 89.21%; MS (ESI) m/z 408.30[M−1]⁻.

Synthesis of7-(benzyloxy)-2-(4-bromophenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one(4)

To a solution of(E)-1-(5-(benzyloxy)-3-hydroxypyridin-2-yl)-3-(4-bromophenyl)prop-2-en-1-one(3, 12.0 g, 29.33 mmol) in ethanol (100 mL) at 0° C., 10% aqueous sodiumhydroxide (8.21 g, 205.3 mmol) was added followed by the addition of 30%aqueous hydrogen peroxide (23.26 mL, 205.3 mmol). The reaction mass wasstirred for 30 min at room temperature (exotherm was observed). Aftercompletion, the reaction mass was cooled and neutralized to pH ˜7 by theaddition of 6 M hydrogen chloride. The solid obtained was filtered,washed with ethanol, pentane and dried under vacuum to afford7-(benzyloxy)-2-(4-bromophenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one(4) as white solid. Yield: 5.0 g, 40%; MS (ESI) m/z 424.14[M+1]⁺.

Synthesis of rac-methyl(7S,8S,9R)-3-(benzyloxy)-6-(4-bromophenyl)-9-hydroxy-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate (6)

A solution of7-(benzyloxy)-2-(4-bromophenyl)-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one(4, 5.0 g, 11.78 mmol) and methyl cinnamate (5, 19.11 g, 117.8 mmol) indichloromethane (250 mL), acetonitrile (125 mL) and methanol (125 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedfor 24 h under 400 watts UV light. After completion, solvent was removedunder reduced pressure and the residue was purified over a plug ofsilica gel eluting the compound with 5% methanol in dichloromethane. Thedesired fractions were concentrated under reduced pressure to affordrac-methyl(7S,8S,9R)-3-(benzyloxy)-6-(4-bromophenyl)-9-hydroxy-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(6) as brown solid. Yield: 6.4 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-3-(benzyloxy)-5a-(4-bromophenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7)

The crude rac-methyl(7S,8S,9R)-3-(benzyloxy)-6-(4-bromophenyl)-9-hydroxy-10-oxo-7-phenyl-6,7,8,9-tetrahydro-6,9-methanooxepino[3,2-b]pyridine-8-carboxylate(6, 6.4 g, 10.91 mmol) was suspended in methanol (120 mL) and treatedwith 25% sodium methoxide in methanol (23.57 mL). The reaction washeated at 80° C. for 4 h. After completion, the solvent was removedunder reduced pressure. The crude was diluted with ammonium chloridesolution and extracted with ethyl acetate. The organic phase wasseparated, dried over sodium sulphate and concentrated under reducedpressure to afford rac-methyl(5aR,6S,7R,8aR)-3-(benzyloxy)-5a-(4-bromophenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7) as brown solid. Yield: 5.3 g, crude.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-bromophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8)

A solution of rac-methyl(5aR,6S,7R,8aR)-3-(benzyloxy)-5a-(4-bromophenyl)-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(7, 5.3 g, 9.03 mmol) in acetonitrile (110 mL) was cooled at 0° C.,acetic acid (5.42 g, 90.37 mmol) and sodium triacetoxyborohydride (11.49g, 54.22 mmol) were added. The resulting mixture was stirred for 12 h atroom temperature. After completion, the reaction mixture was partitionedbetween saturated aqueous sodium bicarbonate solution and ethyl acetate.The organic layer was separated and dried over sodium sulphate, filteredand concentrated to give crude. The crude was purified by silica gelcolumn chromatography eluting with 2-3% in methanol in dichloromethane.The desired fractions were concentrated to afford rac-methyl(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-bromophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8) as white solid. Yield: 2.5 g, 47.0%; MS (ESI) m/z 588.2[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-bromophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-bromophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(8, 0.5 g, 0.849 mmol) in methanol, tetrahydrofuran and water (2:1:1, 10mL), lithium hydroxide (0.20 g, 8.49 mmol) was added and the reactionwas stirred for 6 h at room temperature. After completion, the solventwas evaporated and crude was cooled to 0° C. followed by acidifying with1 M hydrochloric acid to pH 2-3. The precipitated solid was filtered anddried under vacuum to affordrac-(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-bromophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9) as white solid. Yield: 0.42 g, 86%; MS (ESI) m/z 572.14[M−1]⁻.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-bromophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(10)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-bromophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (9, 0.42 g, 0.73 mmol) in dichloromethane (8 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.34 g, 2.19 mmol),hydroxybenzotriazole (0.33 g, 2.19 mmol) and N,N-diisopropylethylamine(0.78 mL, 4.38 mmol) were added and the mixture was stirred for 5 min.Dimethylamine hydrochloride (0.298 g, 3.65 mmol) was then added at thesame temperature and the reaction was stirred for 16 h at roomtemperature. After completion, the reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by silica gel column chromatographyeluting with 2-3% methanol in dichloromethane. The desired fractionswere concentrated to affordrac-(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-bromophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(10) as yellow solid. Yield: 0.35 g, 79.7%; MS (ESI) m/z 601.3[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(11)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-bromophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(10, 0.35 g, 0.582 mmol) in N,N-dimethylformamide (7.0 mL), zinc cyanide(0.409 g, 3.49 mmol) and zinc (0.0045 g, 0.06 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.008 g, 0.0116 mmol),tris(dibenzylideneacetone)dipalladium (0.015 g, 0.0174 mmol) were addedto the reaction and degassing was continued for another 5 min. Thereaction mixture was heated at 140° C. for 4 h. After completion, thereaction mass was diluted with ethyl acetate and washed with cold water.The organic layer was separated and dried over sodium sulphate, filteredand concentrated to give crude. The crude was purified by silica gelcolumn chromatography using 2-3% methanol in dichloromethane as eluent.The desired fractions were concentrated to affordrac-(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(11) as white solid. Yield: 0.26 g, 81.76%; MS (ESI) m/z 548.29[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-3,8,8a-trihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(12)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-(benzyloxy)-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(11, 0.26 g, 0.474 mmol) in ethyl acetate (6.0 mL) and palladiumhydroxide (0.13 g, 0.949 mmol, 50% wet) was added. The reaction wasflushed with hydrogen gas twice and stirred at room temperature for 16 hunder hydrogen pressure. After completion, the reaction mass was passedthrough celite bed and filtrate was concentrated under reduced pressureto affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-3,8,8a-trihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(12) as off white solid. Yield: 0.17 g, 78.34%; MS (ESI) m/z456.32[M−1]⁻.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-3,8,8a-trihydroxy-N,N-dimethyl-6-phenyl-2-(trifluoromethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 29F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-3,8,8a-trihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(12, 0.15 g, 0.327 mmol) in N,N-dimethylformamide (5.0 mL), cesiumcarbonate (0.27 g, 0.819 mmol) and1-(trifluoromethyl)-1-benzo[d][1,2]iodaoxol-3(1H)-one (13, 0.31 g, 0.393mmol) were added at room temperature and reaction mixture was stirred atroom temperature for 2 h. After completion, the reaction mass wasdiluted with ethyl acetate and washed with cold water. The organic layerwas separated and dried over sodium sulphate, filtered and concentratedto give crude. The crude was purified by silica gel columnchromatography using 2-3% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-3,8,8a-trihydroxy-N,N-dimethyl-6-phenyl-2-(trifluoromethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 29F) as yellow solid. Yield: 0.18 g, 10%; MS (ESI) m/z526.4[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 11.16 (s, 1H), 7.48 (d, J=7.6Hz, 2H), 7.31 (d, J=7.4 Hz, 2H), 7.03-7.06 (m, 3H), 6.90-6.98 (m, 3H),6.03 (s, 1H), 5.32 (d, J=4.4 Hz, 1H), 4.64-4.71 (m, 2H), 4.34 (d, J=10.8Hz, 1H), 3.27 (s, 3H), 2.78 (s, 3H).

Example 30Rac-4-((5aR,6S,7S,8R,8aS)-7-(aminomethyl)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 30F)

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(2)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (1, 1.80 g, 3.50 mmol) in dichloromethane (30 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.33 g, 7.00 mmol),hydroxybenzotriazole (1.06 g, 7.00 mmol) and diisopropylethylamine (1.80mL, 10.00 mmol) were added at 0° C. and stirred the mixture for 5 min.Ammonium chloride (1.90 g, 3.50 mmol) was then added and the reactionmixture was stirred for 16 h at room temperature. After completion, thereaction mass was diluted with dichloromethane and washed with coldwater. The organic layer was dried over sodium sulphate, filtered andconcentrated to give crude. The crude was purified by triturating thesolid with ethanol and n-pentane, filtered and dried under vacuum toaffordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(2) as white solid. Yield: 1.10 g, 64%; MS (ESI) m/z 501.26[M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-7-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (3)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(2, 0.60 g, 1.20 mmol) in tetrahydrofuran (20 mL), boranedimethylsulfide complex (0.91 mL, 12.00 mmol) was added at 0° C. Thereaction mixture was then heated at 60-70° C. for 5 h. After completion,reaction mass was quenched with methanol at 0° C. The solvents wereremoved under reduced pressure to affordrac-(5aR,6S,7S,8R,8aS)-7-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(3) as brown liquid. Yield: 0.50 g, (crude); MS (ESI) m/z 487.11 [M+1]⁺.

Synthesis of rac-tert-butyl(((5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-7-yl)methyl)carbamate(4)

To a solution ofrac-(5aR,6S,7S,8R,8aS)-7-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(3, 0.306 g, 0.64 mmol) in dichloromethane (15 mL), triethylamine (0.178mL, 1.28 mmol) and di-tert-butyl dicarbonate (0.167 g, 0.768 mmol) wereadded at room temperature. The reaction mixture was stirred for 3 h atroom temperature. After completion, reaction mass was diluted withdichloromethane and washed with cold water. The organic layer was driedover sodium sulphate, filtered and concentrated under reduced pressureto give crude. The crude was purified by silica gel columnchromatography using 30% ethyl acetate in hexanes as eluent. The desiredfractions were concentrated under reduced pressure to affordrac-tert-butyl(((5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-7-yl)methyl)carbamate(4) as white solid. Yield: 0.125 g, 33.46%; MS (ESI) m/z 587.11[M+1]⁺.

Synthesis of rac-tert-butyl(((5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-7-yl)methyl)carbamate(5)

To a mixture of rac-tert-butyl(((5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-7-yl)methyl)carbamate(4, 0.12 g, 0.20 mmol) in N,N-dimethylformamide (10 mL) at roomtemperature, zinc cyanide (24 mg, 0.20 mmol) and zinc dust (26 mg, 0.40mmol) were added and the mixture was degassed with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (2.90 mg, 0.004 mmol) andtris(dibenzylideneacetone)dipalladium (5.70 mg, 0.006 mmol) were addedto the above reaction and the mixture was degassed with argon foradditional 5 min followed by heating at 130° C. for 3 h. Aftercompletion, the reaction mixture was cooled to room temperature andpassed through a celite bed. Filtrate was concentrated and treated withice-cold water, the solid precipitated was filtered and crude waspurified by silica gel column chromatography using 30% ethyl acetate inhexanes as eluent. The solvent was removed under reduced pressure toafford rac-tert-butyl(((5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-7-yl)methyl)carbamate(5) as white solid. Yield: 0.11 g, 90%; MS (ESI) m/z 534.31[M+1]⁺.

Synthesis ofrac-4-((5aR,6S,7S,8R,8aS)-7-(aminomethyl)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 30F)

To a solution of rac-tert-butyl(((5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-7-yl)methyl)carbamate(5, 0.11 g, 0.20 mmol) in acetonitrile (5 mL), p-toluenesulfonic acid(0.039 g, 0.20 mmol) was added and the reaction was stirred at 35° C.for 16 h. After completion, the reaction mixture was concentrated andcrude was purified by reverse phase HPLC to affordrac-4-((5aR,6S,7S,8R,8aS)-7-(aminomethyl)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 30F) as white solid. Yield: 55 mg, 60%; MS (ESI) m/z434.40[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (d, J=2.0 Hz, 1H), 7.63(d, J=2.0 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.6 Hz, 2H),7.10-6.99 (m, 5H), 6.04 (s, 1H), 4.54 (d, J=4.4 Hz, 1H), 3.95 (d, J=14Hz, 1H), 3.12-3.07 (m, 1H), 2.66 (m, 2H).

Example 31Rac-(5aR,6R,6aS,7aS,7bR)-3-chloro-5a-(4-cyanophenyl)-7b-hydroxy-N,N-dimethyl-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxamide(Cpd. No. 31F)

Synthesis ofrac-(5aR,6R,6aS,7aS,7bR)-5a-(4-bromophenyl)-3-chloro-7b-hydroxy-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxylicacid (2)

To a solution of rac-methyl(5aR,6R,6aS,7aS,7bR)-5a-(4-bromophenyl)-3-chloro-7b-hydroxy-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxylate(1, 38.0 mg, 0.074 mmol) in methanol and water (3:1, 7 mL), lithiumhydroxide (18.0 mg, 0.74 mmol) was added and the reaction was stirredfor 16 h at room temperature. After completion, methanol was removedunder reduced pressure and crude was diluted with water and acidifiedwith 1 M hydrogen chloride to pH ˜3 followed by extraction with ethylacetate (20 mL). The organic layer was separated, dried over sodiumsulphate and concentrated under reduced pressure to affordrac-(5aR,6R,6aS,7aS,7bR)-5a-(4-bromophenyl)-3-chloro-7b-hydroxy-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxylicacid (2) as off white solid. Yield: 23.0 mg, 62%; MS (ESI) m/z496.15[M−1]⁻.

Synthesis ofrac-(5aR,6R,6aS,7aS,7bR)-5a-(4-bromophenyl)-3-chloro-7b-hydroxy-N,N-dimethyl-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxamide(3)

To a solution ofrac-(5aR,6R,6aS,7aS,7bR)-5a-(4-bromophenyl)-3-chloro-7b-hydroxy-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxylicacid (2, 20.0 mg, 0.04 mmol) in dichloromethane (2 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.0 mg,0.12 mmol), 1-hydroxybenzotriazole (16.0 mg, 0.12 mmol) andN,N-diisopropylethylamine (0.042 mL, 0.24 mmol) were added at 0° C. andstirred the mixture for 5 min. Dimethylamine hydrochloride (16.0 mg,0.20 mmol) was then added at same temperature and the mixture wasstirred for 16 h at 40° C. After completion, reaction mass was dilutedwith dichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by Combi-flash (4 g, RediSep column)using 30% ethyl acetate in hexanes as eluent. The desired fractions wereconcentrated under reduced pressure to affordrac-(5aR,6R,6aS,7aS,7bR)-5a-(4-bromophenyl)-3-chloro-7b-hydroxy-N,N-dimethyl-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxamide(3) as yellow solid. Yield: 30 mg, crude; MS (ESI) m/z 525.20[M+1]⁺.

Synthesis ofrac-(5aR,6R,6aS,7aS,7bR)-3-chloro-5a-(4-cyanophenyl)-7b-hydroxy-N,N-dimethyl-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxamide (Cpd. No. 31F)

To a solution ofrac-(5aR,6R,6aS,7aS,7bR)-5a-(4-bromophenyl)-3-chloro-7b-hydroxy-N,N-dimethyl-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxamide(3, 30.0 mg, 0.05 mmol) in N,N-dimethylformamide (5.0 mL), zinc cyanide(17.0 mg, 0.14 mmol) and zinc (7.0 mg, 0.11 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (1.0 mg, 0.001 mmol),tris(dibenzylideneacetone)dipalladium (1.0 mg, 0.001 mmol) were added tothe reaction and degassing was continued for another 5 min. The reactionmixture was heated at 130° C. for 2 h. After completion, the reactionwas cooled to room temperature and passed through celite bed. Thefiltrate was diluted with ethyl acetate and washed with water. Theorganic layer was separated, dried over sodium sulphate and concentratedunder reduced pressure to get the crude. Desired and dicyano compound(side product) were purified by reverse phase prep HPLC. The desiredfractions were concentrated under reduced pressure to affordrac-(5aR,6R,6aS,7aS,7bR)-3-chloro-5a-(4-cyanophenyl)-7b-hydroxy-N,N-dimethyl-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-6a(6H)-carboxamide(Cpd. No. 31F) as white solid. Yield: 2.5 mg, 1.9%; MS (ESI) m/z472.48[M+1]⁺. UPLC: 97.91%; 1H NMR (400 MHz, DMSO-d₆) δ 8.36 (d, J=1.9Hz, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.55 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.5Hz, 2H), 7.23-7.19 (m, 2H), 7.15-7.07 (m, 3H), 6.18 (brs, 1H), 4.44 (s,1H), 2.57 (s, 6H), 2.38 (s, 1H), 1.74 (t, J=6.2 Hz, 1H), 1.51 (t, J=7.6Hz, 1H).

Example 32Rac-(5aR,6S,7R,8aR)-3-chloro-5a-(4-cyanophenyl)-8a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 32F)

Synthesis ofrac-(5aR,6S,7R,8aR)-3-chloro-5a-(4-cyanophenyl)-8a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 26)

To a solution of oxalyl chloride (0.044 mL, 0.525 mmol) in drydichloromethane (1.0 mL) under nitrogen, dimethylsulphoxide (0.052 mL,0.735 mmol) was added drop wise at −78° C. The reaction mixture wasstirred for 30 min and a solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(1, 0.1 g, 0.210 mmol) in dichloromethane (1.0 mL) was added andstirring was continued for another 2 h at the same temperature and thenthe mixture was treated with triethylamine (0.58 mL, 4.20 mmol). Thereaction mass was slowly brought to room temperature and stirred for 15min. The mixture was diluted with water (10 mL) and dichloromethane (20mL). The organic layer was washed with water and brine, dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified by silica gel column chromatography using 50% ethyl acetate inhexanes as eluent. The desired fractions were concentrated under reducedpressure to affordrac-(5aR,6S,7R,8aR)-3-chloro-5a-(4-cyanophenyl)-8a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 32F) as an off-white solid. Yield: 0.01 g, 38% (racemicmixture); MS (ESI) m/z 474.46[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.33(d, J=2.0 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.39(d, J=8.6 Hz, 2H), 7.11-7.06 (m, 3H), 7.02-6.88 (m, 3H), 4.92 (d, J=13.0Hz, 1H), 4.30 (d, J=13.0 Hz, 1H), 3.29 (s, 3H), 2.76 (s, 3H).

Example 33Rac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N,8-trimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 33Fa) andRac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N,8-trimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 33Fb)

Synthesis ofrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(2)

To a solution of oxalyl chloride (0.607 mL, 7.08 mmol) in drydichloromethane (7.5 mL) under nitrogen at −78° C., dimethyl sulfoxide(0.704 mL, 9.91 mmol) was added dropwise. The reaction mixture wasstirred for 30 min and a solution of(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(1, 1.50 g, 2.83 mmol) in dichloromethane (20 mL) was added at −78° C.The reaction was stirred for another 2 h at same temperature and thentriethylamine (3.95 mL, 28.31 mmol) was added. The reaction mass wasslowly brought to room temperature and stirred for 15 min. The mixturewas diluted with water (20 mL) and dichloromethane (40 mL). The organiclayer was washed with water and brine, dried over anhydrous sodiumsulfate, filtered and concentrated. The crude was purified by silica gelcolumn chromatography using 50% ethyl acetate in hexanes as eluent. Thedesired fractions were concentrated under reduced pressure to affordrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(2) as an off-white solid. Yield: 0.5 g, 33%; MS (ESI) m/z 525.19[M−1]⁻.

Synthesis ofrac-(5aR,6S,7R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N,8-trimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(3)

To a solution ofrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(2, 0.3 g, 0.568 mmol) in dry diethyl ether (5.0 mL), methyl magnesiumbromide (3.8 mL, 11.37 mmol) was added dropwise at 0° C. over a periodof 5 min. The reaction mass was slowly brought to room temperature andstirred for 6 h. After completion, the reaction mixture was treated withsaturated aqueous solution of ammonium chloride and extracted with ethylacetate (20 mL). The organic layer was washed with water and brine,dried over anhydrous sodium sulfate, filtered and concentrated to affordrac-(5aR,6S,7R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N,8-trimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(3) as yellow semi solid (mixture of diastereomers). Yield: 0.3 g,crude; MS (ESI) m/z 543.34[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N,8-trimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 33Fa) andRac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N,8-trimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 33Fb)

To a solution affordrac-(5aR,6S,7R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N,8-trimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(3, 0.3 g, 0.55 mmol) in dimethylformamide (25 mL), zinc cyanide (0.37g, 3.3 mmol) and zinc (0.004 g, 0.066 mmol) were added and degassed themixture with argon for 15 min. 1,1′-Bis(diphenylphosphino)ferrocene(0.041 g, 0.011 mmol), tris(dibenzylideneacetone)dipalladium (0.078 g,0.016 mmol) were added to the above reaction and degassing was continuedfor another 5 min followed by heating the reaction mixture at 130° C.for 1 h. After completion, the reaction was cooled to room temperatureand passed through a bed of celite. The filtrate was concentrated andtreated with ice-cold water, the precipitated solid was filtered and thecrude was purified by reverse phase prep HPLC and lyophilized to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N,8-trimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 33Fa) andRac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N,8-trimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 33Fb) Cpd. No. 33Fa: Yield: 0.005 g (off white solid), 1.5%;MS (ESI) m/z 490.52[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (d, J=2.0Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 7.06 (m, 2H), 6.96 (m, 3H), 6.06 (s, 1H), 4.82 (m, 2H), 4.32(d, J=13.2 Hz, 1H), 3.40 (s, 3H), 2.88 (s, 3H), 1.46 (s, 3H).

Cpd. No. 33Fb: Yield: 0.005 g (off white solid), 1.5%; MS (ESI) m/z490.52[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d, J=2.0 Hz, 1H), 7.28(d, J=2.0 Hz, 1H), 7.60 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 7.05(m, 3H), 6.80 (d, J=13.0 Hz, 2H), 5.92 (brs, 2H), 4.07 (d, J=13.8 Hz,1H), 3.93 (d, J=13.8 Hz, 1H), 3.45 (s, 3H), 2.78 (s, 3H), 1.24 (s, 3H).

Example 34Rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8-methylene-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 34F)

Synthesis ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(2)

To a solution of rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(1, 3.0 g, 5.8 mmol) in dimethylsulfoxide (60 mL), lithium chloride(27.2 g, 1.13 mol) was added and stirred the mixture at 150° C. for 24h. After completion, ice cooled water was added and percipitated solidwas filtered. The solid was dissolved in dichloromethane (100 mL),washed with water (2×30 mL) and brine (20 mL). The organics layer wasseparated and dried over anhydrous sodium sulphate before concentrationto dryness. The crude was purified by Combi-flash (12 g, RediSep column)using 20% ethyl acetate in hexanes as eluent. The desired fractions wereconcentrated under reduced pressure to affordrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(2) as off white solid. Yield: 0.85 g, 32.6%; MS (ESI) m/z 455.92[M+1]⁺.

Synthesis ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8-methylene-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol (Cpd. No.34F)

To a solution ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(2, 0.1 g, 0.021 mmol) in dry tetrahydrofuran (2.0 mL), freshly preparedbis(iodozincio)methane (3, 0.17 g, 0.43 mmol) was added drop wise at 0°C. The reaction mass was stirred for 1.5 h at room temperature. Aftercompletion, the reaction mass was treated with saturated solution ofammonium chloride and extracted with diethyl ether. The organic layerwas dried over anhydrous sodium sulphate, filtered and concentratedunder reduced pressure. The crude was purified by Combi-flash (4 g,RediSep column) using 10% ethyl acetate in hexanes as eluent to affordrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8-methylene-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 34F) as white solid. Yield: 0.03 g, 30.0%; MS (ESI) m/z453.93[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (d, J=1.8 Hz, 1H), 7.80(d, J=1.8 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.14-7.06 (m, 5H), 6.95-6.93(m, 2H), 5.98 (s, 1H), 5.79 (s, 1H), 5.42 (s, 1H), 3.47 (dd, J=13.4, 8.2Hz, 1H), 3.15 (dd, J=17.0, 13.2 Hz, 1H), 2.80 (dd, J=17.4, 8.2 Hz, 1H).

Example 35Rac-(5aR,6R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-methoxy-N,N-dimethyl-6-phenyl-5a,8a-dihydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 35F)

Synthesis ofrac-(5aR,6R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-methoxy-N,N-dimethyl-6-phenyl-5a,8a-dihydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.35F)

To a solution ofrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(1, 0.200 g, 0.37 mmol) in acetone (5 mL), potassium carbonate (0.102 g,0.74 mmol) and methyl iodide (0.035 mL, 0.55 mmol) were added andreaction mixture was heated at 50° C. for 16 hours. After completion,reaction mixture was cooled and water (25 mL) was added followed byextraction with ethyl acetate (100 mL). The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified by silica gel column chromatography using 1% methanol indichloromethane as eluent. The desired fractions were concentrated toaffordrac-(5aR,6R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-methoxy-N,N-dimethyl-6-phenyl-5a,8a-dihydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 35F) as off white solid. Yield: 0.11 g, 54%; MS (ESI) m/z541.44[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (d, J=2.0 Hz, 1H), 7.83(d, J=1.6 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.8 Hz, 2H),7.10-6.88 (m, 3H), 6.90 (d, J=6.0 Hz, 2H), 6.64 (s, 1H), 4.35 (s, 1H),4.08 (s, 3H), 3.12 (s, 3H), 2.73 (s, 3H).

Example 36Rac-(4aR,5S,6R,7R,7aS)-3-chloro-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 36F)

Synthesis ofrac-(4aR,5S,6R,7R,7aS)-3-chloro-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a, 5,6,7, 7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 36F)

To a solution ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-3-chloro-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(1, 0.04 g, 0.07 mmol) in N,N-dimethylformamide (1.0 mL), zinc cyanide(0.052 g, 0.45 mmol) and zinc (0.001 g, 0.008 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.001 g, 0.001 mmol),tris(dibenzylideneacetone)dipalladium (0.002 g, 0.002 mmol) were addedto the reaction and degassing was continued for another 5 min. Thereaction mixture was heated at 140° C. for 2 h. After completion, thereaction mass was diluted with ethyl acetate and washed with cold water.The organic layer was separated and dried over sodium sulphate, filteredand concentrated to give crude. The crude was purified by silica gelcolumn chromatography using 2-3% methanol in dichloromethane as eluent.The desired fractions were concentrated to afford rac-(4aR,5S,6R,7R,7aS)-3-chloro-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 36F) as white solid. The crude was purified by Prep HPLC.Yield: 0.013 g, 36% (racemic mixture); MS (ESI) m/z 479.5 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆₎ δ 7.54 (d, J=8.6 Hz, 2H), 7.32 (d, J=8.6 Hz, 2H),7.01 (m, 3H), 6.81 (d, J=7.2 Hz, 2H), 5.85 (s, 1H), 5.48 (d, J=6.2 Hz,1H), 4.78 (t, J=6.8 Hz, 1H), 4.45 (d, J=13.4 Hz, 1H), 4.11 (dd, J=13.4,7.36 Hz, 1H), 3.78 (s, 3H), 3.20 (s, 3H), 2.74 (s, 3H).

Example 37Rac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-3-chloro-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 37F)

Synthesis ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-3-chloro-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a, 5,6,7, 7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 37F)

To a solution ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(1, 0.1 g, 0.2 mmol) in acetonitrile (3 mL), N-chlorosuccinimide (0.04g, 0.30 mmol) was added and the reaction was stirred at 45° C. for 4 h.After completion, reaction mass was diluted with ethyl acetate andwashed with cold water. The organic layer was separated and dried oversodium sulphate, filtered and concentrated to give crude. The crude waspurified by silica gel column chromatography using 5% methanol indichloromethane as eluent. The desired fractions were concentrated toaffordrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-3-chloro-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 37F) as white solid. Yield: 0.055 g, 51.8%; (racemic mixture);MS (ESI) m/z 532.5[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.27 (d, J=8.6 Hz,2H), 7.04 (m, 5H), 6.81 (d, J=7.2 Hz, 2H), 5.74 (s, 1H), 5.41 (d, J=6.2Hz, 1H), 4.77 (t, J=6.9 Hz, 1H), 4.38 (d, J=13.2 Hz, 1H), 4.03 (dd,J=13.2, 7.6 Hz, 1H), 3.78 (s, 3H), 3.19 (s, 3H), 2.73 (s, 3H).

Example 38Rac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-6,7-dihydrospiro[cyclopenta[4,5]furo[3,2-b]pyridine-8,2′-oxetan]-8a(5aH)-ol(Cpd. No. 38F)

Synthesis ofrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-6,7-dihydrospiro[cyclopenta[4,5]furo[3,2-b]pyridine-8,2′-oxetan]-8a(5aH)-ol(Cpd. No. 38F)

To a solution of trimethyl sulfoxonium iodide (2, 0.96 g, 4.3 mmol) inN,N-dimethylformamide (10 mL), potassium tert-butoxide (0.49 g, 4.3mmol) was added and stirred for 30 minutes at 50° C. A solution ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(1, 0.35 g, 1.0 mmol) in N,N-dimethylformamide was added to the abovemixture at 50° C. and reaction was stirred for 16 h at 50° C. Aftercompletion, the reaction mixture was cooled and diluted with ethylacetate and washed with cold water. The organic layer was separated anddried over anhydrous sodium sulphate, filtered and concentrated to givecrude. The crude was purified by Combi-flash (12 g, RediSep column)using 10% ethyl acetate in hexanes as eluent. The desired fractions wereconcentrated under reduced pressure to affordrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-6,7-dihydrospiro[cyclopenta[4,5]furo[3,2-b]pyridine-8,2′-oxetan]-8a(5aH)-ol(Cpd. No. 38F) as white solid. Yield: 0.032 g, 8.6%; MS (ESI) m/z483.92[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (d, J=2.0 Hz, 1H), 7.80(d, J=2.0 Hz, 1H), 7.25 (d, J=8.6 Hz, 2H), 7.14 (d, J=8.7 Hz, 2H),7.10-6.99 (m, 5H), 5.78 (s, 1H), 4.62-4.57 (m, 2H), 3.62-3.51 (m, 2H),2.78-2.72 (m, 1H), 2.66-2.53 (m, 1H).

Example 39Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-7-((methylamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 39F)

Synthesis ofrac-4-((5aR,6S,7R,8R,8aS)-3-chloro-7-formyl-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(2)

To a vigorously stirred solution ofrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-7-(hydroxymethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(1, 272 mg, 0.630 mmol) in dichloromethane (100 mL) at 0° C. was addedsaturated aqueous sodium bicarbonate (30 mL), 0.5 M potassium bromide inwater (1.25 mL, 0.63 mmol) and then TEMPO (4.9 mg, 0.030 mmol). Theresulting slightly orange biphasic mixture was stirred vigorously at 0°C. for 10 min and then aqueous solution of sodium hypochlorite in water(0.34 mL of 10-15% available chlorine) was added dropwise. The resultingorange biphasic mixture was stirred vigorously at 0° C. for 15 min. Moresodium hypochlorite (0.34 mL of 10-15% available chlorine) was added andstirring at 0° C. was continued for an additional 20 min. The layerswere separated in separatory funnel. The aqueous layer was extractedonce with dichloromethane. The combined organics were dried over sodiumsulfate, filtered, and concentrated on a rotary evaporator down to ˜5mL. This solution ofrac-4-((5aR,6S,7R,8R,8aS)-3-chloro-7-formyl-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(2) was used in the next reaction without further manipulation orpurification. MS (ESI) m/z 433.1[M+1]⁺.

Synthesis ofrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-7-((methylamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 39F)

To a stirred solution ofrac-4-[(5aR,6S,7R,8R,8aS)-3-chloro-7-formyl-8,8a-dihydroxy-6-phenyl-7,8-dihydro-6H-cyclopenta[4,5]furo[1,2-b]pyridin-5a-yl]benzonitrile(2, 135 mg, 0.310 mmol) in DICHLOROMETHANE (2.5 mL) was addedsequentially: 1,2-DICHLOROETHANE (5 mL), methylamine (2 M inTETRAHYDROFURAN) (0.31 mL, 0.62 mmol), and then sodiumtriacetoxyborohydride (132 mg, 0.62 mmol). The resulting mixture wascapped and stirred at room temperature for 1.5 h. Saturated aqueousSodium bicarbonate (2 mL) was added with vigorous stirring. The layerswere separated in a separatory funnel and the aqueous layer extractedonce with DICHLOROMETHANE. The combined organics were evaporated todryness, dissolved in DMSO and methanol, filtered, and purified viapreparatory HPLC (15-35% acetonitrile in water with 0.1% TRIFLUOROACETICACID). Fractions containing the desired product were loaded onto aStrata X-C ion exchange column from Phenomenex. The column was elutedsequentially with water, acetonitrile, methanol, and then 5% ammoniumhydroxide in methanol. Fractions containing the desired product werecombined, concentrated on a rotary evaporator and dried under highvacuum to affordrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-7-((methylamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 39F) as an off-white solid. Yield: 34 mg, 24%; MS (ESI) m/z448.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (d, J=2.0 Hz, 1H), 7.64(d, J=2.0 Hz, 1H), 7.52-7.46 (m, 2H), 7.37-7.31 (m, 2H), 7.13-6.96 (m,5H), 6.07 (s, 1H), 4.50 (d, J=4.1 Hz, 1H), 4.00 (d, J=14.1 Hz, 1H), 3.21(ddt, J=13.0, 8.1, 3.6 Hz, 1H), 2.69 (dd, J=12.0, 8.5 Hz, 1H), 2.24 (s,3H).

Example 40Rac-4-((5aR,6S,7R,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 40Fa),rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 40Fb), andrac-4-((5aR,6S,7S,8S,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 40Fc)

Synthesis ofrac-4-((5aR,6S,7R,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 40Fa),rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 40Fb), andrac-4-((5aR,6S,7S,8S,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 40Fc)

To a stirred solution ofrac-4-((5aR,6S,7R,8R,8aS)-3-chloro-7-formyl-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(1, 135 mg, 0.31 mmol) in dichloromethane (2.5 mL) was addedsequentially: 1,2-dichloroethane (5 mL), dimethylamine (2 M intetrahydrofuran) (0.31 mL, 0.62 mmol), and then sodiumtriacetoxyborohydride (132 mg, 0.62 mmol). The resulting mixture wascapped and stirred at room temperature for 1.5 h. Saturated aqueoussodium bicarbonate (2 mL) was added with vigorous stirring. The layerswere separated in a separatory funnel and the aqueous layer extractedonce with dichloromethane. The combined organics were evaporated todryness, dissolved in dimethyl sulfoxide and methanol, filtered, andpurified via preparatory HPLC (15-37% acetonitrile in water with 0.1%trifluoroacetic acid). Fractions containing the desired products wereloaded onto a Strata X-C ion exchange column from Phenomenex. The columnwas eluted sequentially with water, acetonitrile, methanol, and then 5%ammonium hydroxide in methanol. Fractions containing the desired productwere combined, concentrated on a rotary evaporator and dried under highvacuum to affordrac-4-((5aR,6S,7R,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 40Fa) as a white solid. Yield: 4 mg, 3%; MS (ESI) m/z462.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (d, J=2.0 Hz, 1H),7.57-7.46 (m, 5H), 7.31-7.26 (m, 2H), 7.24-7.12 (m, 3H), 6.80 (s, 1H),4.40 (d, J=11.7 Hz, 1H), 4.08 (d, J=7.1 Hz, 1H), 2.43 (tdd, J=11.0, 6.9,4.0 Hz, 1H), 1.99 (s, 7H), 1.90 (t, J=11.3 Hz, 1H). Andrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 40Fb) as a white solid. Yield: 30 mg, 21%; MS (ESI) m/z462.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (d, J=2.0 Hz, 1H), 7.63(d, J=2.0 Hz, 1H), 7.51-7.46 (m, 2H), 7.39-7.33 (m, 2H), 7.12-6.97 (m,5H), 6.12 (s, 1H), 5.33 (s, 1H), 4.44 (d, J=3.8 Hz, 1H), 3.94 (d, J=14.0Hz, 1H), 3.22 (ddt, J=13.8, 10.1, 3.4 Hz, 1H), 2.61 (dd, J=12.3, 10.0Hz, 1H), 2.21 (s, 6H), 1.98 (dd, J=12.4, 2.9 Hz, 1H). Andrac-4-((5aR,6S,7S,8S,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 40Fc) as a white solid. Yield: 8 mg, 6%; MS (ESI) m/z462.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (d, J=2.0 Hz, 1H), 7.81(d, J=2.1 Hz, 1H), 7.68-7.62 (m, 2H), 7.46 (d, J=7.7 Hz, 2H), 7.06 (dd,J=4.8, 1.9 Hz, 3H), 6.81-6.74 (m, 2H), 6.18 (s, 1H), 5.51 (s, 1H), 4.50(d, J=6.0 Hz, 1H), 3.00 (d, J=13.3 Hz, 1H), 2.68-2.58 (m, 1H), 2.22-2.13(m, 1H), 2.07 (s, 6H), 2.02 (dd, J=12.6, 4.0 Hz, 1H).

Example 41Rac-4-((5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 41Fa),rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 41Fb), andrac-4-((5aR,6S,7S,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 41Fc)

Synthesis ofrac-4-((5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 41Fa),rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 41Fb), andrac-4-((5aR,6S,7S,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 41Fc)

To a stirred solution ofrac-4-((5aR,6S,7R,8R,8aS)-3-chloro-7-formyl-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(1, 200 mg, 0.46 mmol) in dichloromethane (3 mL) was added sequentially:1,2-dichloroethane (3 mL), pyrrolidine (65 mg, 0.92 mmol) in1,2-dichloroethane (1 mL) and then sodium triacetoxyborohydride (195 mg,0.92 mmol). The resulting mixture was capped and stirred at roomtemperature for 1 h. Saturated aqueous sodium bicarbonate (2 mL) wasadded with vigorous stirring. The layers were separated in a separatoryfunnel and the aqueous layer extracted once with dichloromethane. Thecombined organics were evaporated to dryness, dissolved in dimethylsulfoxide and methanol, filtered, and purified via preparatory HPLC(15-37% acetonitrile in water with 0.1% trifluoroacetic acid). Fractionscontaining the desired products were loaded onto a Strata X-C ionexchange column from Phenomenex. The column was eluted sequentially withwater, acetonitrile, methanol, and then 5% ammonium hydroxide inmethanol. Fractions containing the desired product were concentrated ona rotary evaporator and lyophilized to dryness from 50% acetonitrile inwater to affordrac-4-((5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 41Fa) as a slightly yellow solid. Yield: 10 mg, 4%; MS (ESI)m/z 488.2[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (d, J=1.9 Hz, 1H),7.59-7.44 (m, 5H), 7.33-7.25 (m, 2H), 7.23-7.10 (m, 3H), 6.80 (s, 1H),5.09 (s, 1H), 4.40 (d, J=11.7 Hz, 1H), 4.11 (d, J=7.0 Hz, 1H), 2.47-2.39(m, 1H), 2.39-2.30 (m, 2H), 2.24-2.05 (m, 4H), 1.64 (d, J=4.8 Hz, 4H).Andrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 41Fb) as a white solid. Yield: 30 mg, 13%; MS (ESI) m/z488.2[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (dd, J=2.0, 0.6 Hz, 1H),7.63 (dd, J=2.0, 0.6 Hz, 1H), 7.52-7.46 (m, 2H), 7.38-7.32 (m, 2H),7.12-6.96 (m, 5H), 6.11 (d, J=0.6 Hz, 1H), 5.46 (s, 1H), 4.47 (d, J=3.9Hz, 1H), 3.97 (d, J=14.1 Hz, 1H), 3.23 (ddt, J=13.6, 9.6, 3.2 Hz, 1H),2.83 (dd, J=12.2, 9.6 Hz, 1H), 2.62-2.53 (m, 2H), 2.48-2.40 (m, 2H),2.20 (dd, J=12.2, 2.8 Hz, 1H), 1.74-1.63 (m, 4H). Andrac-4-((5aR,6S,7S,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 41Fc) as a white solid. Yield: 10 mg, 4%; MS (ESI) m/z488.2[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (d, J=2.1 Hz, 1H), 7.81(d, J=2.0 Hz, 1H), 7.68-7.61 (m, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.06 (dd,J=4.8, 1.9 Hz, 3H), 6.77 (dd, J=6.7, 2.9 Hz, 2H), 6.13 (s, 1H), 5.52 (s,1H), 4.52 (d, J=5.9 Hz, 1H), 3.02 (d, J=13.3 Hz, 1H), 2.69-2.57 (m, 1H),2.47-2.18 (m, 7H), 1.58 (d, J=6.2 Hz, 4H).

Example 42Rac-(1R,2R,3S,3aR,8bS)-8b-azido-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3-dihydro-1H-cyclopenta[b]benzofuran-2-carboxamide(Cpd. No. 42F)

Synthesis ofrac-(1R,2R,3S,3aR,8bS)-8b-azido-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3-dihydro-1H-cyclopenta[b]benzofuran-2-carboxamide(Cpd. No. 42F)

To a solution of rac-(1R,2R,3S,3aR,8bS)-1,8b-dihydroxy-6-methoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3-dihydro-1H-cyclopenta[b]benzofuran-2-carboxamide(150 mg, 0.32 mmol) in chloroform (1.5 mL) was added sodium azide (61mg, 0.95 mmol), followed by perchloric acid (0.08 mL, 0.95 mmol). Theorange solution was stirred at 25° C. for 90 m. The reaction mixture wasthen poured carefully into a solution of saturated sodium bicarbonate(10 mL). The heterogeneous solution was extracted with dichloromethane(3×5 mL). The organic material was washed with brine and dried overmagnesium sulfate, filtered, and solvent removed under reduced pressure.Purification by silica gel chromatography eluting with hexanes and ethylacetate affordedrac-(1R,2R,3S,3aR,8bS)-8b-azido-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3-dihydro-1H-cyclopenta[b]benzofuran-2-carboxamide(Cpd. No. 42F) as a white solid. Yield 89%. MS (ESI) m/z 501.2[M+1]⁺;NMR (400 MHz, CD₃OD) δ 7.54 (d, J=4.8 Hz, 1H), 7.12-7.04 (m, 5H),6.77-6.73 (m, 4H), 6.69-6.65 (m, 2H), 4.82 (d, J=5.1 Hz, 1H), 4.28 (d,J=8.1 Hz, 1H), 4.04 (dd, J=7.8, 4.8 Hz, 1H), 3.87 (s, 3H), 3.77 (s, 3H).3.24-2.64 (bs, 6H)

Example 43 Rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-fluoro-8-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(Cpd. No. 43F)

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-fluoro-8-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(Cpd. No. 43F)

Dissolved rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(50 mg, 0.10 mmol) in dichloromethane (1 mL). The solution was cooled to−10° C. and (diethylamino)sulfur trifluoride (47 mg, 0.29 mmol) wasadded. The mixture was stirred at −10° C. for 3 h and then quenched witha few drops of methanol. Saturated aqueous ammonium chloride (5 mL) anddichloromethane (5 mL) were added. The layers were separated and theaqueous material was extracted with dichloromethane (3×5 mL). Thecombined organic material was washed with brine, dried over magnesiumsulfate, filtered and solvent removed under reduced pressure.Purification by silica gel chromatography afforded rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-fluoro-8-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(Cpd. No. 43F) as a white solid. Yield 24%. MS (ESI) m/z 501.9[M+1]⁺; ¹HNMR (400 MHz, Chloroform-d) δ 8.33 (d, J=1.8 Hz, 1H), 7.51 (dd, J=1.4,1.4 Hz, 1H), 7.36-7.23 (m, 3H), 7.20-7.06 (m, 3H), 6.99 (dt, J=8.6, 1.6Hz, 2H), 6.85-6.78 (m, 2H), 5.40 (ddd, J=16.9, 7.1, 1.1 Hz, 1H), 4.19(dd, J=14.0, 1.9 Hz, 1H), 3.94 (dtd, J=14.0, 7.2, 1.2 Hz, 1H), 3.64 (d,J=1.2 Hz, 3H).

Example 44Rac-(1R,2R,3S,3aR,8bS)-8b-amino-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-carboxamide(Cpd. No. 44F)

Synthesis ofRac-(1R,2R,3S,3aR,8bS)-8b-amino-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-carboxamide (Cpd. No.44F)

To a solution ofrac-(1R,2R,3S,3aR,8bS)-8b-azido-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-carboxamide(55 mg, 0.11 mmol) in methanol (1 mL) was added palladium on carbon (2mg, 0.11 mmol). The solution was sparged with hydrogen gas for 1 minthen stirred at room temperature under an atmosphere of hydrogen. After6 h the reaction mixture was filtered through celite, the filter cakewas washed several times with methanol. The solvent was removed underreduced pressure and purification via reverse phase HPLC yieldedrac-(1R,2R,3S,3aR,8bS)-8b-amino-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-carboxamide(Cpd. No. 44F) as an off-white solid. Yield 48%. MS (ESI) m/z342.9[M+1]⁺; NMR (400 MHz, CD₃OD) δ 7.65 (d, J=5.1 Hz, 1H), 7.07-7.01(m, 5H) 6.86 (d, J=7.1 Hz, 1H), 6.81 (d, J=1.2 Hz, 1H), 6.67 (dd, J=5.1,1.2 Hz, 1H), 5.15 (d, J=5.7 Hz, 1H), 4.64 (d, J=7.5 Hz), 4.36 (dd,J=7.5, 5.7 Hz, 1H), 3.86 (s, 3H), 3.74 (s, 3H), 3.28 (s, 3H), 2.91 (s,3H)

Example 45Rac-(1R,2R,3S,3aR,8bS)-8b-acetamido-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-carboxamide(Cpd. No. 45F)

Synthesis ofrac-(1R,2R,3S,3aR,8bS)-8b-acetamido-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-carboxamide(Cpd. No. 45F)

A solution ofrac-(1R,2R,3S,3aR,8bS)-8b-amino-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-carboxamide(10 mg, 0.02 mmol) in dichloromethane (0.4 ml) and triethylamine (0.01ml, 0.07 mmol) was added acetyl chloride (0.01 ml, 0.07 mmol) dropwisevia micropipette. After 1 h the mixture was diluted with dichloromethaneand poured onto saturated aqueous sodium bicarbonate (5 mL), and theaqueous material was extracted with dichloromethane (3×5 mL). Thecombine organic material was washed with brine (30 ml), dried overmagnesium sulfate, filtered and solvent removed under reduced pressure.The product was purified via reverse phase HPLC to affordrac-(1R,2R,3S,3aR,8bS)-8b-acetamido-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-carboxamide(Cpd. No. 45F). Yield: 62%. MS (ESI) m/z 517.3[M+1]⁺; ¹H NMR (400 MHz,Chloroform-d) δ 7.59 (d, J=8.5 Hz, 1H), 7.12-6.99 (m, 6H), 6.83 (dd,J=6.5, 3.1 Hz, 2H), 6.79-6.73 (m, 2H), 6.64 (d, J=2.3 Hz, 1H), 6.52 (dd,J=8.5, 2.4 Hz, 1H) 5.72 (s, 1H), 5.32 (d, J=9.7 Hz, 1H), 4.60 (d, J=13.1Hz, 1H), 4.02 (dd, J=13.2, 9.6 Hz, 1H), 3.84 (2,3H), 3.75 (s, 3H),3.38-3.18 (bs, 3H), 2.89-2.96 (bs, 3H), 2.11-1.92 (m, 1H).

Example 46 Rac-dimethyl2-[[(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-6,7-dihydrocyclopenta[4,5]furo[1,2-b]pyridin-7-yl]methyl]propanedioate(Cpd. No. 46F)

Synthesis ofrac-4-((5aR,6R,8aR)-3-chloro-8a-hydroxy-7-methylene-8-oxo-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(2)

Rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-6,7-dihydrocyclopenta[4,5]furo[1,2-b]pyridin-8-one(95 mg, 0.21 mmol) was stirred in anhydrous tetrahydrofuran (3 mL) at−78° C. and (diisopropylamino)lithium (0.44 mL, 0.85 mmol) was addeddropwise. After 15 minutes solid dimethyl(methylene)ammonium iodide (192mg, 1.04 mmol) was added in 1 portion. The mixture was allowed togradually warm to room temperature. After 3 h at this temperature thereaction mixture was diluted reaction with ethyl acetate (20 mL) andpoured onto saturated aqueous sodium bicarbonate (30 mL). The layerswere separated and aqueous material extracted with ethyl acetate (3×15mL). The combine organic material was washed with brine, dried overmagnesium sulfate, filtered, and solvent removed under reduced pressure.Purification via silica gel chromatography eluting with hexanes andethyl acetate affordedrac-(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-7-methylene-6-phenyl-6H-cyclopenta[4,5]furo[1,2-b]pyridin-8-one(2) as a brown residue. Yield 56%. MS (ESI) m/z 415.1[M+1]⁺.

Synthesis of rac-dimethyl2-[[(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-6,7-dihydrocyclopenta[4,5]furo[1,2-b]pyridin-7-yl]methyl]propanedioate(Cpd. No. 46F)

Rac-(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-7-methylene-6-phenyl-6H-cyclopenta[4,5]furo[1,2-b]pyridin-8-one(11 mg, 0.02 mmol) and dimethyl malonate (0.01 mL, 0.11 mmol) weredissolved in dry methanol (0.5 mL). Sodium methoxide (0.01 mL, 0.07mmol) was added dropwise via syringe and the solution was stirred atroom temperature. After 2 h the reaction was neutralized by the additionof 2 drops of 6 M hydrochloric acid. The mixture was diluted with water(5 mL), and was extracted with ethyl acetate (3×5 mL). The combinedorganic material was dried over magnesium sulfate, filtered and solventremoved under reduced pressure. Purification via reverse phase HPLCafforded rac-dimethyl2-[[(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-6,7-dihydrocyclopenta[4,5]furo[1,2-b]pyridin-7-yl]methyl]propanedioate(Cpd. No. 46F) as an off-white solid. Yield: 71%. MS (ESI) m/z602.3[M+1]⁺; ¹H NMR (400 MHz, Chloroform-d) δ 8.26 (s, 1H), 7.57 (s,1H), 7.39-7.22 (m, 6H), 7.22-7.09 (m, 4H), 6.98-6.90 (m, 2H), 6.86-6.79(m, 2H) 3.80 (dd, J=9.1, 6.1 Hz, 2H), 3.74-3.54 (m, 8H), 3.42-3.27 (m,3H), 2.10-1.96 (m, 2H).

Example 47Rac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(Cpd. No. 47F)

Synthesis ofrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylmethanesulfonate (2)

To a solution ofrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(1, 558 mg, 10.9 mmol) in pyridine (9 mL) at 0° C. was addedmethanesulfonyl chloride (0.10 ml, 1.31 mmol). The reaction was allowedto reach room temperature and stirred 16 h. An additional 0.05 ml ofmethanesulfonyl chloride was added and the reaction stirred anadditional 24 h, at which point the reaction mixture was poured ontowater and ethyl acetate. The aqueous material was extracted with ethylacetate (3×15 ml), and the combined organic were washed with 3 M aqueouscopper sulfate (30 ml), brine (30 ml), dried over magnesium sulfate,filtered and solvent removed under reduced pressure. The crude residuewas purified by silica gel chromatography eluting with hexanes and ethylacetate to affordrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylmethanesulfonate (2) as an off-white residue. Yield 39%. MS (ESI) m/z538.1[M+1]⁺.

Synthesis ofrac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(Cpd. No. 47F)

To a solution ofrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylmethanesulfonate (2, 242 mg, 0.45 mmol) in dimethyl sulfoxide (2 mL) wasadded potassium cyanide (294 mg, 4.51 mmol) at room temperature. After2.5 h the mixture was diluted with acetonitrile, filtered throughcelite, placed in a test tube and purified by reverse phase HPLC toaffordrac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(Cpd. No. 47F). Yield: 85%; MS (ESI) m/z 468.1[M+1]⁺; ¹H NMR (400 MHz,CDCl₃) δ 7.68 (dd, J=1.9, 0.5 Hz, 1H), 7.35 (dd, J=1.9, 0.6 Hz, 1H),7.37-7.20 (m, 1H), 7.22-7.04 (m, 1H), 7.15 (s, 1H), 7.08-6.94 (m, 3H),4.81 (s, 1H), 4.18-4.06 (m, 1H), 3.88 (dd, J=7.5, 3.7 Hz, 1H), 2.95(ddd, J=13.1, 11.8, 7.6 Hz, 1H), 2.67-2.53 (m, 2H), 2.06-1.97 (m, 1H),1.25 (td, J=7.1, 0.6 Hz, 1H).

Example 48Rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8-ethynyl-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 48F)

Synthesis ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbaldehyde(2)

To a solution ofrac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(75 mg, 0.16 mmol) in dichloromethane (1 ml) at −78° C. was added asolution of diisobutylaluminum hydride (0.32 mL, 0.32 mmol) dropwise.After 30 m the reaction was warmed to room temperature, stirred for 30m, then cooled to 0° C. and quenched by the dropwise addition of 3 Mhydrochloric acid. The reaction was diluted with ethyl acetate (10 mL)and saturated aqueous Rochelle's salt (10 mL). The layers were separatedand the aqueous material was extracted with ethyl acetate (2×10 mL). Thecombined organic material was washed with saturated aqueous Rochelle'ssalt (10 mL), brine (20 mL), dried over magnesium sulfate, filtered, andsolvent was removed under reduced pressure. Purification by silica gelchromatography eluting with hexanes and ethyl acetate afforded aninseparable mixture of epimeric aldehydes that was carried on to thefollowing step without further purification. MS (ESI) m/z 470.0[M+1]⁺.

Synthesis ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8-ethynyl-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol (Cpd. No.48)

A solution containing a mixture of epimeric aldehydes at c-8rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbaldehyde(50 mg) and methanol (1 ml) was cooled to 0° C. and1-diazo-1dimethoxyphosphoryl-propane-2-one (Horner-Wadsworth-Emmonsreagent, 0.76 ml, 0.53 mmol) was added followed by potassium carbonate(208 mg, 0.64 mmol). The mixture was stirred for 3 h and solvent wasremoved under reduced pressure. The residue was taken up indichloromethane (5 ml) and saturated aqueous sodium bicarbonate (5 ml).The layers were separated and the aqueous layer was extracted withdichloromethane (2×5 ml). The combined organic material was washed withbrine, dried over magnesium sulfate, filtered, and solvent removed underreduced pressure. The residue was purified via reverse phase HPLC toafford a 3:1 mixture of alkynesrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8-ethynyl-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 48). MS (ESI) m/z 468.2[M+1]⁺; NMR (400 MHz, CDCl₃) Majordiastereomer: δ 8.24 (d, J=1.9 Hz, 1H), 7.47 (dd, J=1.9, 0.5 Hz, 1H).7.33-7.19 (m), 7.19-7.06 (m), 7.06-6.98 (m), 6.98-6.90 (m), 3.70-3.56(m, 2H), 2.77-2.59 (m, 3H). Minor diastereomer: δ 8.20 (d, J=1.9 Hz,1H), 7.57 (dd, J=1.9, 0.5 Hz, 1H), 7.33-7.19 (m), 7.19-7.06 (m),7.06-6.98 (m), 6.98-6.90 m) 4.28 (dd, J=11.7, 6.2 Hz, 1H), 3.82 (dt,J=6.6, 3.3 Hz, 1H), 2.49 (ddd, J=12.8, 6.3, 3.6 Hz, 1H), 2.12 (d, J=3.3Hz, 1H).

Example 49 Rac-methyl(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-cyano-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(Cpd. No. 49F)

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-((methylsulfonyl)oxy)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(1, 200 mg, 0.39 mmol) in pyridine (4 mL) was added methanesulfonylchloride (0.04 mL, 0.46 mmol) dropwise. The reaction was stirred at roomtemperature overnight. More methanesulfonyl chloride (0.04 mL, 0.46mmol) was added dropwise. The reaction was stirred at room temperatureover the weekend. The resulting mixture was concentrated, re-dilutedwith dichloromethane and washed with water. The combined organics weredried over magnesium sulfate, filtered and concentrated. The crude waspurified via flash chromatography (silica, ethyl acetate/hexane=0-40%)to afford rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-((methylsulfonyl)oxy)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2) as a white solid. Yield: 201 mg, 87%; MS (ESI) m/z 596.1[M+1]⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 8.35 (d, J=2.0 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H),7.36-7.22 (m, 2H), 7.20-7.04 (m, 5H), 7.03-6.91 (m, 2H), 6.76 (s, 1H),5.76 (s, 1H), 5.69 (d, J=5.9 Hz, 1H), 4.47 (dd, J=14.3, 6.0 Hz, 1H),4.26 (d, J=14.3 Hz, 1H), 3.57 (s, 3H), 3.15 (s, 3H).

Synthesis of rac-methyl(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-cyano-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(Cpd. No. 49F)

Rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-((methylsulfonyl)oxy)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2, 81 mg, 0.14 mmol) and potassium cyanide (18 mg, 0.27 mmol) weredissolved in dimethylsulfoxide (0.50 mL). The reaction was stirred atroom temperature for 4 h. The mixture was purified on reverse phase HPLC(acetonitrile/water=15-75%) to afford rac-methyl(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-cyano-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(Cpd. No. 49F) as a pink solid. Yield: 45 mg, 63%; MS (ESI) m/z527.0[M+1]⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.37 (d, J=2.0 Hz, 1H), 7.88(d, J=2.0 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.19-7.03 (m, 4H), 6.93 (d,J=9.6 Hz, 2H), 6.81 (s, 1H), 4.29-4.08 (m, 2H), 3.76 (d, J=12 Hz, 1H),3.54 (s, 3H).

Example 50 Rac-methyl(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(Cpd. No. 50F)

Synthesis of rac-methyl(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(Cpd. No. 50F)

A suspension of rac-methyl(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-cyano-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(1, 450 mg, 0.86 mmol), zinc (30 mg, 0.47 mmol) and zinc cyanide (322mg, 2.74 mmol) in N,N-dimethylformamide (10 mL) and water (1 mL) waspurged with argon for 5 min. Dppf (45 mg, 0.08 mmol) andtris(dibenzylideneacetone)dipalladium(0) (47 mg, 0.05 mmol) were added.The reaction was microwaved at 120° C. for 1 h. The mixture was dilutedwith dichloromethane and washed with water. The combined organics weredried over magnesium sulfate, filtered and concentrated. The crude waspurified via flash chromatography (silica, ethyl acetate/hexanes=0-35%)to afford rac-methyl(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(Cpd. No. 50F) as a white solid. Yield: 400 mg, 99%; MS (ESI) m/z472.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (d, J=2.0 Hz, 1H), 7.90(d, J=2.0 Hz, 1H), 7.76-7.57 (m, 2H), 7.38 (d, J=8.1 Hz, 2H), 7.07 (dt,J=4.9, 1.8 Hz, 3H), 6.98-6.93 (m, 2H), 6.89 (s, 1H), 4.34-4.22 (m, 2H),3.89-3.79 (m, 1H), 3.54 (s, 3H).

Example 51Rac-(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 51F)

Synthesis ofrac-(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (2)

To a solution of rac-methyl(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(15 mg, 0.03 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) wasadded 2 M lithium hydroxide (1 mL, 2 mmol). The reaction was stirred atroom temperature for 5 m. The reaction was acidified with 1 Mhydrochloric acid and the organic volatiles were evaporated. The mixturewas diluted with water and extracted with dichloromethane. The combinedorganics were dried over magnesium sulfate, filtered and concentrated.The crude was used for next step without further purification. Yield: 15mg, crude; MS (ESI) m/z 458.2[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 51F)

To a solution ofrac-(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (2, 30 mg, 0.07 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (39 mg,0.20 mmol), 1-hydroxybenzotriazole hydrate (31 mg, 0.20 mmol) indichloromethane (4 mL) at 0° C. was added N,N-diisopropylethylamine(0.08 mL, 0.46 mmol) and N-methylmethanamine hydrochloride (11 mg, 0.13mmol). The reaction was stirred at room temperature overnight. Themixture was diluted with dichloromethane and washed with aqueoussaturated sodium bicarbonate solution. The combined organics were driedover magnesium sulfate, filtered and concentrated. The crude waspurified via column chromatography (silica, ethyl acetate/hexane=0-60%),followed by reverse phase HPLC (acetonitrile/water=15-60%) to affordrac-(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 51F) as a white solid. Yield: 13.7 mg, 43%; MS (ESI) m/z485.5[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J=2.0 Hz, 1H), 7.91(d, J=2.0 Hz, 1H), 7.73-7.65 (m, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.13-7.04(m, 3H), 6.91 (s, 1H), 6.88-6.81 (m, 2H), 4.48 (dd, J=12.7, 10.4 Hz,1H), 3.97-3.85 (m, 2H), 3.26 (s, 3H), 2.76 (s, 3H).

Example 52Rac-(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 52F)

Synthesis ofrac-(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 52F)

To a solution ofrac-(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (30 mg, 0.07 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (38 mg, 0.20 mmol), 1-hydroxybenzotriazole hydrate (30 mg,0.20 mmol) and ammonium chloride (9 mg, 0.16 mmol) in dichloromethane (4mL) was added N,N-diisopropylethylamine (0.09 mL, 0.52 mmol). Thereaction was stirred at room temperature overnight. The mixture wasdiluted with dichloromethane and washed with aqueous saturated sodiumbicarbonate solution. The combined organics were dried over magnesiumsulfate, filtered and concentrated. The crude was purified via columnchromatography (silica, ethyl acetate/hexane=0-50%) to affordrac-(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 52F) as a white solid. Yield: 16 mg, 53%; MS (ESI) m/z457.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d, J=2.0 Hz, 1H),7.95-7.87 (m, 2H), 7.74 (d, J=8.2 Hz, 2H), 7.35 (d, J=8.6 Hz, 3H), 7.09(dd, J=5.0, 1.9 Hz, 3H), 6.95 (dd, J=6.8, 2.9 Hz, 2H), 6.90 (d, J=0.6Hz, 1H), 4.06 (dd, J=13.3, 10.8 Hz, 1H), 3.89 (d, J=10.7 Hz, 1H), 3.62(d, J=13.3 Hz, 1H).

Example 53Rac-(3aR,3bS,8aR,9R,9aR)-8a-(4-bromophenyl)-6-chloro-3b-hydroxy-9-phenyl-1,3a,3b,8a,9,9a-hexahydro-2H-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-2-one(Cpd. No. 53F)

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (2)

To rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(1, 111 mg, 0.22 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) atroom temperature was added 2 M lithium hydroxide (1.6 mL, 3.2 mmol) andthe mixture was stirred at 40° C. After 1 h the mixture was cooled downto room temperature and stirred for another 1.5 h. The mixture wasacidified with 2 M hydrochloric acid (1.8 mL) and diluted with ethylacetate and water. The aqueous phase was extracted with ethyl acetatethrice, and the combined organic phases were dried (sodium sulfate),filtered and concentrated. The crude material was pure by LCMS and usedin the next step without further purification. Yield: 120 mg, crude; MS(ESI) m/z 502.0[M+1]⁺.

Synthesis ofrac-(3aR,3bS,8aR,9R,9aR)-8a-(4-bromophenyl)-6-chloro-3b-hydroxy-9-phenyl-1,3a,3b,8a,9,9a-hexahydro-2H-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-2-one(Cpd. No. 53F)

To cruderac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (2, 108 mg, 0.215 mmol) in toluene (2 mL) at room temperature wereadded molecular sieves (40 mg), diphenyl phosphoryl azide (60 μL, 0.28mmol) and triethylamine (46 μL, 0.33 mmol) and the mixture was stirredat room temperature for 15 m, then at 110° C. for 2 h. Then the mixturewas allowed to cool down to room temperature, diluted withdichloromethane, and washed with brine. The aqueous phase was extractedthrice with dichloromethane and the combined organic phases were washedwith brine, then dried (sodium sulfate), filtered, and concentrated.Purification by column chromatography (silica, 0-10%methanol/dichloromethane) followed by repeated prep-HPLC (C18,acetonitrile/water+0.1% trifluoroacetic acid) gaverac-(3aR,3bS,8aR,9R,9aR)-8a-(4-bromophenyl)-6-chloro-3b-hydroxy-9-phenyl-1,3a,3b,8a,9,9a-hexahydro-2H-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-2-one(Cpd. No. 53F) as a white fluffy solid. Yield: 24 mg, 22%; MS (ESI)499.2[M+1]⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.36 (d, J=2.0 Hz, 1H), 8.27(bs, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.37 (d, J=8.2 Hz, 2H), 7.17-7.11 (m,3H), 7.07 (d, J=8.2 Hz, 2H), 7.01-6.69 (m, 2H), 6.33 (s, 1H), 5.49 (d,J=9.3 Hz, 1H), 4.91 (dd, J=9.3, 9.7 Hz, 1H), 3.53 (d, J=9.7 Hz, 1H).

Example 54Rac-4-((3aR,3bS,8aR,9R,9aR)-6-chloro-3b-hydroxy-2-oxo-9-phenyl-1,2,3a,3b,9,9a-hexahydro-8aH-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-8a-yl)benzonitrile(Cpd. No. 54F)

Synthesis ofrac-4-((3aR,3bS,8aR,9R,9aR)-6-chloro-3b-hydroxy-2-oxo-9-phenyl-1,2,3a,3b,9,9a-hexahydro-8aH-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-8a-yl)benzonitrile(Cpd. No. 54F)

In a 0.5-2 mL microwave vialrac-(3aR,3bS,8aR,9R,9aR)-8a-(4-bromophenyl)-6-chloro-3b-hydroxy-9-phenyl-1,3a,3b,8a,9,9a-hexahydro-2H-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]-furo[3,2-b]pyridin-2-one(1, 13.7 mg, 0.0274 mmol) was dissolved in N,N-dimethylformamide (1 mL)and water (0.1 mL). Zinc cyanide (10.8 mg, 0.092 mmol) and zinc (1 mg,0.02 mmol) were added, and the mixture was degassed by bubbling argonthrough it for 5 min. 1,1′-Bis(diphenylphosphino)ferrocene (4.6 mg,0.0083 mmol) and tris(dibenzylideneacetone)dipalladium(0) (3.8 mg,0.0042 mmol) were added and the mixture was incubated at 100° C. for 30min, then for another 15 min. Then the mixture was diluted withdichloromethane and washed with water. The aqueous phase was extractedwith dichloromethane twice. Then the combined organic phases were dried(sodium sulfate), filtered and concentrated. Purification by HPLC (C18,Acetonitrile/water+0.1% trifluoroacetic acid) gaverac-4-((3aR,3bS,8aR,9R,9aR)-6-chloro-3b-hydroxy-2-oxo-9-phenyl-1,2,3a,3b,9,9a-hexahydro-8aH-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-8a-yl)benzonitrile(Cpd. No. 54F) as an off-white solid. Yield: 5.6 mg, 46%; MS (ESI)445.9[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (d, J=2.0 Hz, 1H), 8.30(s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.67 (d, J=8.7 Hz, 2H), 7.32 (d, J=8.7Hz, 2H), 7.15-7.10 (m, 3H), 7.02-6.97 (m, 2H), 6.43 (s, 1H), 5.53 (d,J=8.9 Hz, 1H), 4.97 (dd, J=9.9, 8.9 Hz, 1H), 3.60 (d, J=9.9 Hz, 1H).

Example 55Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 55F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 55F)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(1, 320 mg, 0.619 mmol) in tetrahydrofuran (4 mL) at 0° C. was addedlithium aluminum hydride (LAH) (27 mg, 0.71 mmol) and the mixture wasstirred at 0° C. for 30 min, then warmed up to rt. After another 1.5 hanother 13 mg (0.34 mmol) LAH were added, and stirring at roomtemperature was continued. After another 30 min another 13 mg (0.34mmol) LAH were added. After 3 h (total reaction time) water and brinewere carefully added, and the mixture was diluted with ethyl acetate.The phases were separated and the aq. phase was extracted with ethylacetate thrice. The combined organic phases were washed with brine, thendried (sodium sulfate), filtered and concentrated. The crude product waspurified by column chromatography (silica, methanol/dichloromethane,product eluted at 5% methanol). Yield: 165 mg, ca. 90% pure, ca. 49%yield; Ca. 25 mg of this material were repurified by HPLC (C18,acetonitrile/water+0.1% trifluoroacetic acid) to giverac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 55F) as a fluffy white solid. MS (ESI) m/z 487.9[M+1]⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 8.17 (d, J=2.1 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H),7.21 (d, J=8.7 Hz, 2H), 7.14-6.97 (m, 7H), 4.50 (d, J=3.8 Hz, 1H), 3.88(d, J=14.2 Hz, 1H), 3.55 (dd, J=10.6, 9.1 Hz, 1H), 3.43 (dd, J=10.6, 3.1Hz, 1H), 3.21-3.09 (m, 1H).

Example 56Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-7-(hydroxymethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 56F)

Synthesis ofrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-7-(hydroxymethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 56F)

In a 0.5-2 mL microwave vialrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(1, 24.7 mg, 0.0505 mmol) was dissolved in N,N-dimethylformamide (0.50mL) and water (0.05 mL). Zinc cyanide (19 mg, 0.16 mmol) and zinc (1.8mg, 0.028 mmol) were added, and the mixture was degassed by bubblingargon through it for 5 min. 1,1′-Bis(diphenylphosphino)ferrocene (2.7mg, 0.0049 mmol) and tris(dibenzylideneacetone)dipalladium(0) (2.8 mg,0.0030 mmol) were added, and the mixture was incubated at 100° C. for 30min. Then the mixture was diluted with ethyl acetate and washed withwater. The organic phase was dried (sodium sulfate), filtered andconcentrated. Purification by column chromatography (silica,methanol/dichloromethane, product eluted at 5% methanol) andsubsequently by HPLC (C18, acetonitrile/water+0.1% trifluoroacetic acid)gaverac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-7-(hydroxymethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 56F). Yield: 15.5 mg, 71%; MS (ESI) m/z 435.3[M+1]⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 8.19 (d, J=2.0 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H),7.49 (d, J=8.6 Hz, 2H), 7.32 (d, J=8.6 Hz, 2H), 7.14-6.96 (m, 5H), 4.52(d, J=3.9 Hz, 1H), 3.94 (d, J=14.1 Hz, 1H), 3.57 (dd, J=10.7, 9.6 Hz,1H), 3.45 (dd, J=10.7, 2.9 Hz, 1H), 3.26-3.14 (m, 1H).

Example 57Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-methyl-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 57F)

Synthesis ofrac-((5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-7-yl)methylmethanesulfonate (2)

In a flame-dried vial,rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(1, 60 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL).Triethylamine (0.13 mL, 1.3 mmol) was added, and the mixture was cooleddown to −78° C. Methanesulfonyl chloride (10.5 μL, 15.5 mg, 0.135 mmol)was added, and the mixture was stirred at −78° C. for 30 min, thenwarmed up to 0° C. Another 4 μL (6 mg, 0.05 mmol) methanesulfonylchloride were added, and the mixture was stirred for another 5 min(conversion was monitored by TLC). Then the reaction was quenched withwater and diluted with dichloromethane. The phases were separated andthe organic phase was extracted with dichloromethane thrice. Thecombined organic phases were dried (sodium sulfate), filtered andconcentrated. The so-obtained crude product 2 was used without furtherpurification. MS (ESI) m/z 566.0 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-methyl-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd.No. 57F)

In a flame-dried flask,rac-((5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-7-yl)methylmethanesulfonate (2, ca. 69 mg, 0.12 mmol) was dissolved intetrahydrofuran (1.2 mL) and cooled to 0° C. Lithium aluminum hydride(LAH) (5.1 mg, 0.13 mmol) was added, and the mixture was stirred at 0°C. After 20 min, another 6.5 mg (0.17 mmol) LAH were added, and themixture was warmed up to room temperature After another 1 h 25 minanother 6 mg (0.16 mmol) LAH were added. After 2.5 h (total reactiontime) the mixture was cooled down to 0° C., and water was carefullyadded. The mixture was diluted with dichloromethane and filtered. Thenthe phases were separated and the aq. phase was extracted withdichloromethane thrice. The combined organic phases were dried (sodiumsulfate), filtered and concentrated. The crude product was purified byrepeated column chromatography (silica, methanol/dichloromethane,product eluted at 4% methanol, followed by ethyl acetate/hexane, producteluted at 50% ethyl acetate). The so-obtained product was repurified byHPLC (C18, acetonitrile/water+0.1% trifluoroacetic acid) to giverac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-methyl-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 57F) as a fluffy white solid. Yield: 6.5 mg, 11%, 2 steps; MS(ESI) m/z 472.1[M+1]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 8.17 (d, J=2 Hz, 1H),7.60 (d, J=2 Hz, 1H), 7.20 (d, J=9 Hz, 2H), 7.22-7.19 (m, 4H), 7.04-7.01(m, 3H), 4.27 (d, J=4 Hz, 1H), 3.80 (d, J=14 Hz, 1H), 3.13-3.07 (m, 1H),0.96 (d, J=7 Hz, 3H).

Example 58 Rac-methyl(5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7-fluoro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(Cpd. No. 58F)

Synthesis of rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2)

To oxalyl chloride (2 M in dichloromethane, 0.86 mL, 1.7 mmol) indichloromethane (8 mL) at −78° C. was added dimethyl sulfoxide (0.14 mL,0.15 g, 2.0 mmol) and the mixture was stirred for 10 min. Thenrac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(1, 726 mg, 1.40 mmol) in 8 mL dichloromethane was added and the mixturewas stirred for 30 min. Then triethylamine (1.1 mL, 0.80 g, 7.9 mmol)was added and the mixture was allowed to warm up to room temperaturewithin 1.5 h. Water was added, and the phases were separated. Theaqueous phase was extracted with dichloromethane thrice, and thecombined organic phases were dried (sodium sulfate), filtered andconcentrated. The crude material was purified by column chromatography(silica, 0% to 100% ethyl acetate/hexane, then 0% to 10%methanol/dichloromethane). Yield: 217 mg, 38%; MS (ESI) m/z 514.1[M+1]⁺.

Synthesis of rac-methyl(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-7-fluoro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(3)

The starting material rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2, 88 mg, 0.17 mmol) was dissolved in tetrahydrofuran (1.2 mL) andcooled to −78° C. Potassium tert-butoxide (25 mg, 0.22 mmol) in 0.2 mLtetrahydrofuran was added dropwise, and the mixture was stirred at −78°C. for 10 min, then at 0° C. for 5 min, then cooled to −78° C. again.N-Fluorobenzenesulfonimide (70 mg, 0.22 mmol) in 0.3 mL tetrahydrofuranwas added and the mixture was slowly warmed up to 0° C. within 2 h andstirred at this temp for another 1 h. Another 12 mg (0.038mmol)N-fluorobenzenesulfonimide in 0.05 mL tetrahydrofuran were addedand the reaction mixture was stirred for a few more minutes until thereaction was complete. Then 2 mL aqueous ammonium chloride solution wasadded, and the mixture was diluted with dichloromethane. The phases wereseparated, and the aqueous phase was extracted with dichloromethanethrice. The combined organic phases were dried (sodium sulfate),filtered and concentrated. The crude material contained the desiredproduct (MS (ESI) m/z 532.1[M+1]⁺) and was directly used in the nextstep.

Synthesis of rac-methyl(5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7-fluoro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(Cpd. No. 52)

The crude starting material rac-methyl(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-7-fluoro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(3, crude product from the previous step) was dissolved in acetonitrile(1.7 mL) and acetic acid (1.7 mL), and sodium triacetoxyborohydride (362mg, 1.71 mmol) were added. The mixture was stirred at room temperature.After 15 min complete conversion was observed by LCMS. Water wascarefully added, and the mixture was extracted with dichloromethanethrice. The combined organic phases were dried (sodium sulfate),filtered and concentrated. Purification by column chromatography(silica, ethyl acetate/hexane, product eluted at 55% ethyl acetate) gave59 mg of material, which was repurified by HPLC (C18,acetonitrile/water+0.1% trifluoroacetic acid) to give rac-methyl(5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7-fluoro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(Cpd. No. 58F) as fluffy white solid. Yield: 39.5 mg, 43%, two steps; MS(ESI) m/z 534.2[M+1]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 8.23 (d, J=2 Hz, 1H),7.46 (d, J=2 Hz, 1H), 7.35 (d, J=9 Hz, 2H), 7.27 (d, J=9 Hz, 2H),7.21-7.14 (m, 5H), 5.33 (d, J=29 Hz, 1H), 4.48 (d, J=22 Hz, 1H), 3.30(s, 3H).

Example 59 Rac-methyl(5aR,6S,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-7-fluoro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(Cpd. No. 59F)

Synthesis of rac-methyl(5aR,6S,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-7-fluoro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(Cpd. No. 59F)

In a 0.5-2 mL MW vial rac-methyl(5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7-fluoro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(1, 56 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (1.5 mL)and water (0.15 mL). Zinc cyanide (40 mg, 0.34 mmol) and zinc (2.7 mg,0.042 mmol) were added, and the mixture was degassed by bubbling argonthrough it for 5 min. 1,1′-Bis(diphenylphosphino)ferrocene (11.6 mg,0.0209 mmol) and tris(dibenzylideneacetone)dipalladium(0) (9.6 mg, 0.010mmol) were added and the mixture was incubated at 100° C. for 30 min.Then the mixture was diluted with dichloromethane and washed with water.The aqueous phase was extracted with dichloromethane once more. Then thecombined organic phases were dried (sodium sulfate), filtered andconcentrated. Purification by column chromatography (silica, ethylacetate/hexane, product eluted at 6% ethyl acetate) gave rac-methyl(5aR,6S,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-7-fluoro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(Cpd. No. 59F) as off-white solid. Yield: 36.5 mg, 72%; MS (ESI) m/z481.0[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J=2.0 Hz, 1H), 7.60(d, 8.6 Hz, 2H, AB-system), 7.56 (d, J=8.6 Hz, 2H, AB-system), 7.52 (d,J=2.0 Hz, 1H), 7.19-7.12 (m, 5H), 7.03 (s, 1H), 5.96 (d, J=7.4 Hz, 1H),5.36 (dd, J=28.6, 7.4 Hz, 1H), 4.52 (d, J=22.8 Hz, 1H), 3.31 (s, 3H).

Example 60Rac-(2aS,3S,3aR,8bS,8cR)-3a-(4-bromophenyl)-6-chloro-3-phenyl-2a,3,3a,8c-tetrahydrooxeto[3″,2′:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-8b(2H)-ol(Cpd. No. 60F)

Synthesis ofrac-((5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-7-yl)methylmethanesulfonate (2)

In a flame-dried vial,rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(1, 64 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL).Triethylamine (0.14 mL, 0.14 g, 1.3 mmol) was added, and the mixture wascooled down to −78° C. Methanesulfonyl chloride (11.5 μL, 17.0 mg, 0.149mmol) was added, and the mixture was stirred at −78° C. for 30 min, thenwarmed up to 0° C., and stirred for another 30 min. Then the reactionwas quenched with water. The phases were separated and the aqueous phasewas extracted with dichloromethane thrice. The combined organic phaseswere dried (sodium sulfate), filtered and concentrated. The crudeproduct was directly used in the next step. MS (ESI) m/z 566.2[M+1]⁺.

Synthesis ofrac-(2aS,3S,3aR,8bS,8cR)-3a-(4-bromophenyl)-6-chloro-3-phenyl-2a, 3,3a,8c-tetrahydrooxeto[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-8b(2H)-ol(Cpd. No. 60F)

In a flame-dried vial,rac((5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-7-yl)methylmethanesulfonate (2, crude product from previous step, ca. 74 mg, 0.13mmol) was dissolved in methanol (2.6 mL) and cooled to 0° C. Sodiummethanolate (25% in methanol, 0.30 mL, 1.3 mmol) was added, and themixture was stirred at room temperature. After 20 min the mixture waswarmed up to 50° C. After another 20 min the mixture was warmed up to75° C. After another 30 min complete conversion was observed by LCMS.The mixture was allowed to cool down to room temperature, diluted withdichloromethane and washed with water. The aqueous phase was extractedwith dichloromethane and the combined organic phases were dried (sodiumsulfate), filtered and concentrated. Purification by columnchromatography (silica, ethyl acetate/hexane, product eluted at 45%ethyl acetate) gaverac-(2aS,3S,3aR,8bS,8cR)-3a-(4-bromophenyl)-6-chloro-3-phenyl-2a,3,3a,8c-tetrahydrooxeto[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-8b(2H)-ol(Cpd. No. 60F) as a white solid. Yield: 30.9 mg, 50%, two steps; MS(ESI) m/z 470.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J=2.0 Hz,1H), 7.78 (d, J=2.0 Hz, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.15-7.07 (m, 3H),7.02 (d, J=8.8 Hz, 2H), 7.00-6.96 (m, 2H), 6.21 (s, 1H), 5.55 (d, J=6.1Hz, 1H), 4.75 (dd, J=5.8, 5.8 Hz, 1H), 4.13 (d, J=8.0 Hz, 1H), 3.95 (dd,J=5.8, 2.9 Hz, 1H), 3.79-3.72 (m, 1H).

Example 61Rac-(2aS,3S,3aR,8bS,8cR)-3a-(4-bromophenyl)-6-chloro-3-phenyl-2a,3,3a,8c-tetrahydrooxeto[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-8b(2H)-ol(Cpd. No. 61F)

Synthesis ofrac-4-((2aS,3S,3aR,8bS,8cR)-6-chloro-8b-hydroxy-3-phenyl-2a,3,8b,8c-tetrahydrooxeto[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-3a(2H)-yl)benzonitrile (Cpd. No. 61F)

In a 0.5-2 mL MW vialrac-(2aS,3S,3aR,8bS,8cR)-3a-(4-bromophenyl)-6-chloro-3-phenyl-2a,3,3a,8c-tetrahydrooxeto[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-8b(2H)-ol(1, 21.8 mg, 0.046 mmol) was dissolved in N,N-dimethylformamide (0.7 mL)and water (0.07 mL). Zinc cyanide (18.2 mg, 0.155 mmol) and zinc (1.2mg, 0.018 mmol) were added, and the mixture was degassed by bubblingargon through it for 5 min. 1,1′-Bis(diphenylphosphino)ferrocene (5.1mg, 0.0092 mmol) and tris(dibenzylideneacetone)dipalladium(0) (4.2 mg,0.0046 mmol) were added and the mixture was incubated at 100° C. for 30min. Then the mixture was diluted with dichloromethane and washed withwater. The aqueous phase was extracted with dichloromethane once more.Then the combined organic phases were dried (sodium sulfate), filteredand concentrated. Purification by column chromatography (silica,hexane/ethyl acetate, product eluted at 55% ethyl acetate) gaverac-(2aS,3S,3aR,8bS,8cR)-3a-(4-bromophenyl)-6-chloro-3-phenyl-2a,3,3a,8c-tetrahydrooxeto[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-8b(2H)-ol(Cpd. No. 61F) as a white solid. Yield: 7.8 mg, 40%; MS (ESI) m/z417.0[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (d, J=2.0 Hz, 1H), 7.83(d, J=2.0 Hz, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H),7.14-7.08 (m, 3H), 7.00-6.96 (m, 2H), 6.30 (s, 1H), 5.58 (d, J=6.0 Hz,1H), 4.76 (dd, J=5.8, 5.8 Hz, 1H), 4.19 (d, J=8.0 Hz, 1H), 3.95 (dd,J=5.8, 2.8 Hz, 1H), 3.84-3.78 (m, 1H).

Example 62Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(methoxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 62F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(methoxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 62F)

In a flame-dried vial, cruderac-((5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-7-yl)-methylmethanesulfonate (1, ca. 266 mg, 0.469 mmol) was dissolved in methanol(9.4 mL) and cooled to 0° C. Sodium methanolate (25% in methanol, 1.1mL, 4.8 mmol) was added, and the mixture was stirred at roomtemperature. After 20 min the mixture was warmed up to 50° C. Afteranother 15 min the mixture was warmed up to 75° C. After another 25 mincomplete conversion was observed by LCMS. The mixture was allowed tocool down to room temperature, diluted with dichloromethane and washedwith water. The aqueous phase was extracted with dichloromethane and thecombined organic phases were dried (sodium sulfate), filtered andconcentrated. Purification by column chromatography (silica, ethylacetate/hexane) followed by repeated preparative TLC (silica, ethylacetate/Hexane=2/1, then dichloromethane/Methanol=9/1) gaverac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(methoxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 62F) as a white solid. Yield: 7.1 mg, 3%); MS (ESI) m/z502.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (d, 2.0 Hz, 1H), 7.61 (d,J=2.0 Hz, 1H), 7.21 (d, J=8.9 Hz, 2H), 7.13-07.08 (m, 4H), 7.06-6.99 (m,3H), 6.02 (s, 1H), 5.30 (d, J=5.6 Hz, 1H), 4.42 (dd, J=5.6 Hz, 4.3 Hz,1H), 3.88 (d, J=14.0 Hz, 1H), 3.52 (dd, J=9.2, 9.2 Hz, 1H), 3.30-3.18(m, 2H), 3.23 (s, 3H).

Example 63Rac-(1aS,3S,3aR,8bS)-3a-(4-bromophenyl)-6-chloro-3-phenyl-1a,2,3,3a-tetrahydro-oxireno[2″,3″:1′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine(Cpd. No. 63F)

Synthesis ofrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a, 6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (2)

The starting materialrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(1, 200 mg, 0.438 mmol) was dissolved in acetonitrile (2.2 mL) andacetic acid (2.2 mL). Sodium triacetoxyborohydride (928 mg, 4.38 mmol)was added, and the resulting mixture was stirred at room temperature.After 30 min water was carefully added, and the mixture was extractedwith dichloromethane three times. The combined organic phases were dried(sodium sulfate), filtered and concentrated. Purification by columnchromatography (silica, ethyl acetate/hexane, product eluted at 50%ethyl acetate) gaverac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(2) as off-white solid. Yield: 201 mg, 100%; MS (ESI) m/z 458.3[M+1]⁺.

Synthesis ofrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylmethanesulfonate (3)

In a flame-dried flask,rac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(2, 20 mg, 0.044 mmol) were dissolved in dichloromethane (0.5 mL).Triethylamine (0.05 mL, 0.5 mmol) was added, and the mixture was cooleddown to −78° C. Methanesulfonyl chloride (4.8 μL, 7.1 mg, 0.062 mmol)was added, and the mixture was stirred at −78° C. for 30 min, thenwarmed up to 0° C. Another 5 μL (7 mg, 0.06 mmol) methanesulfonylchloride were added, followed by another 2 μL (3 mg, 0.03 mmol)methanesulfonyl chloride. After 1 h 10 min (total reaction time) thereaction was quenched with water and diluted with dichloromethane. Thephases were separated, and the aqueous phase was extracted withdichloromethane thrice. The combined organic phases were dried (sodiumsulfate), filtered and concentrated. The crude product was purified bycolumn chromatography (silica, ethyl acetate/hexane, product eluted at50% ethyl acetate) to giverac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylmethanesulfonate (3). Yield: 17.7 mg, 76%, white solid.

Synthesis ofrac-(1aS,3S,3aR,8bS)-3a-(4-bromophenyl)-6-chloro-3-phenyl-1a,2,3,3a-tetrahydro-oxireno[2″,3″:1′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine(Cpd. No. 63F)

In a flame-dried vial,rac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylmethanesulfonate (3, 17.7 mg, 0.033 mmol) was dissolved in toluene (0.5mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene (25.0 μL, 25.5 mg, 0.168 mmol)was added, and the mixture was stirred at 50° C. for 45 min, and thenwarmed up to 65° C. After another 45 min the mixture was warmed up to80° C. After another 45 min another 25 μL (25.5 mg, 0.168 mmol)1,8-diazabicyclo[5.4.0]undec-7-ene were added, and stirring at 80° C.was continued for another 15 min. Then the mixture was cooled down toroom temperature and the reaction was quenched with saturated ammoniumchloride solution. The mixture was extracted with dichloromethanethrice, and the combined organic phases were dried (sodium sulfate),filtered and concentrated. Purification by column chromatography(silica, ethyl acetate/hexane, product eluted at 30% ethyl acetate) andsubsequent preparative TLC (silica, ethyl acetate/hexane=1/1) gaverac-(1aS,3S,3aR,8bS)-3a-(4-bromophenyl)-6-chloro-3-phenyl-1a,2,3,3a-tetrahydro-oxireno[2″,3″:1′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine(Cpd. No. 63F) as a white solid. Yield: 4.0 mg, 28%; MS (ESI) m/z440.0[M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J=1.9 Hz, 1H), 7.29 (d,J=1.9 Hz, 1H), 7.21 (d, J=8.9 Hz, 2H), 7.18-7.08 (m, 5H), 7.07-7.03 (m,2H), 4.60 (dd, J=12.1, 9.3 Hz, 1H), 4.27 (d, J=3.7 Hz, 1H), 2.72 (ddd,J=14.8, 9.3, 3.7 Hz, 1H), 2.57 (dd, J=14.8, 12.1 Hz, 1H).

Example 64(4bS,5R,6R,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 64F)

Synthesis of 3-chloro-5-((4-methoxybenzyl)oxy)isonicotinonitrile (2)

To a solution of 3,5-dichloroisonicotinonitrile (1, 15.00 g, 87.20 mmol)in tetrahydrofuran (300 mL) at 0° C., 60% sodium hydride (6.90 g, 174.40mmol) was added followed by addition of (4-methoxyphenyl)methanol (13.20g, 95.70 mmol) and the reaction mixture was stirred at room temperaturefor 2 h. After completion, the mixture was quenched with ice cold water(100 mL) and the mixture was extracted with ethyl acetate (100 mL). Theorganic layer was washed with water and brine, dried over anhydroussodium sulfate, filtered and concentrated to afford3-chloro-5-((4-methoxybenzyl)oxy)isonicotinonitrile (2) as white solid.Yield: 18.0 g, 75%; MS (ESI) m/z 275.16[M+1]⁺.

Synthesis of 3-methoxy-5-((4-methoxybenzyl)oxy)isonicotinonitrile (3)

To a solution of 3-chloro-5-((4-methoxybenzyl)oxy)isonicotinonitrile (2,14.00 g, 51.10 mmol) in methanol (160 mL), sodium methoxide (25% inmethanol, 20 mL) was added. The reaction mixture was refluxed at 80° C.for 2 h. After completion, solvent was removed under reduced pressure.The mixture was quenched with ice cold water (100 mL) and extracted withethyl acetate (100 mL). The organic layer was washed with water andbrine, dried over anhydrous sodium sulfate, filtered and concentrated.The crude was purified by silica gel column chromatography using 50%ethyl acetate in hexanes as eluents. The desired fractions wereconcentrated to afford3-methoxy-5-((4-methoxybenzyl)oxy)isonicotinonitrile (3) as white solid.Yield: 6.3 g, 45%; MS (ESI) m/z 271.23[M+1]⁺.

Synthesis of 1-(3-hydroxy-5-methoxypyridin-4-yl)ethan-1-one (4)

To a solution of 3-methoxy-5-((4-methoxybenzyl)oxy)isonicotinonitrile(3, 6.30 g, 23.30 mmol) in dry tetrahydrofuran (250 mL) at 0° C., methylmagnesium bromide (69.90 mL, 209.73 mmol) was added dropwise over aperiod of 30 min. The reaction mass was slowly brought to roomtemperature and stirred for additional 12 h. After completion, thereaction mass was quenched with 6 M hydrochloric acid to pH ˜3 andstirred for 3 h. The mixture was diluted with ethyl acetate (100 mL),water (50 mL) and basified with NaHCO₃ up to pH-10. The organic layerwas separated, washed with water, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The crude was purifiedby silica gel column chromatography using 60% ethyl acetate in hexanesas eluent. The desired fractions were concentrated to afford1-(3-hydroxy-5-methoxypyridin-4-yl)ethan-1-one (4) as light yellowsolid. Yield: 2.0 g, 51.2%; MS (ESI) m/z 168.17[M+1]⁺.

Synthesis of(E)-3-(4-bromophenyl)-1-(3-hydroxy-5-methoxypyridin-4-yl)prop-2-en-1-one(6)

To a solution of 1-(3-hydroxy-5-methoxypyridin-4-yl)ethan-1-one (4, 2.00g, 11.90 mmol) in methanol (10 mL), sodium hydroxide (1.40 g, 35.90mmol) was added followed by addition of 4-bromobenzaldehyde (5, 2.19 g,11.90 mmol). The reaction was heated to reflux for 10 min. Aftercompletion, the reaction mass was cooled to room temperature, dilutedwith water (20 mL) and extracted with 5% methanol in dichloromethane(100 mL). The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated. The solid obtained was triturated withpentane, filtered and dried under vacuum to afford(E)-3-(4-bromophenyl)-1-(3-hydroxy-5-methoxypyridin-4-yl)prop-2-en-1-one(6) as yellow solid. Yield: 3.2 g, 76.0%; MS (ESI) m/z 334.14[M+1]⁺.

Synthesis of(2-(4-bromophenyl)-3-hydroxy-5-methoxy-4H-pyrano[2,3-c]pyridin-4-one (7)

To a solution of(E)-3-(4-bromophenyl)-1-(3-hydroxy-5-methoxypyridin-4-yl)prop-2-en-1-one(6, 4.60 g, 13.80 mmol) in ethanol (70 mL) and dichloromethane (10 mL)at 0° C., 10% aqueous sodium hydroxide solution (39 mL, 96.60 mmol) wasadded followed by the addition of 30% aqueous hydrogen peroxide (9.80mL, 96.60 mmol). The reaction mass was stirred for 30 min at roomtemperature (exotherm was observed). After completion, the reaction masswas cooled and neutralized to pH ˜7 by the addition of 6 M hydrogenchloride. The mixture was extracted with ethyl acetate (100 mL). Theorganic layer was washed with water and brine, dried over anhydroussodium sulfate, filtered and concentrated. The solid obtained wastriturated with ethanol, filtered and dried under vacuum to afford of(2-(4-bromophenyl)-3-hydroxy-5-methoxy-4H-pyrano[2,3-c]pyridin-4-one (7)as yellow solid. Yield: 1.4 g, 29.2%; MS (ESI) m/z 348.07[M+1]⁺.

Synthesis of rac-methyl(2R,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(9)

A solution of(2-(4-bromophenyl)-3-hydroxy-5-methoxy-4H-pyrano[2,3-c]pyridin-4-one (7,1.40 g, 4.04 mmol) and methyl cinnamate (8, 6.53 g, 10.40 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedunder 400 watts UV light for 18 h. After completion, solvent was removedunder reduced pressure and the residue was purified over a plug ofsilica gel eluting the compound with ethyl acetate. The desiredfractions were concentrated under reduced pressure to afford rac-methyl(2R,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(9) as dark brown solid. Yield: 1.80 g, crude.

Synthesis of rac-methyl(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(10)

The crude compound rac-methyl(2R,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(9, 1.80 g) was suspended in methanol (25 mL) and treated with 25%sodium methoxide in methanol (15 mL). The reaction was heated at 80° C.for 3 h. After completion, the solvent was removed under reducedpressure. The crude was diluted with ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and concentrated under reduced pressure to affordrac-methyl(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(10) as brown solid. Yield: 1.4 g, crude.

Synthesis of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(11)

To a solution of sodium triacetoxyborohydride (3.40 g, 16.50 mmol),rac-methyl(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(10, 1.40 g, 2.75 mmol) in acetonitrile (20 mL), acetic acid (1.65 g,27.50 mmol) was added. The resulting mixture was stirred for 4 h at roomtemperature. After completion, the reaction mixture was partitionedbetween saturated aqueous sodium bicarbonate solution and ethyl acetate.The organic layer was separated, dried over sodium sulphate, filteredand concentrated under reduced pressure to get the crude. The crude waspurified by silica gel column chromatography using 50% ethyl acetate inhexanes as eluents. The desired fractions were concentrated underreduced pressure to afford rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(11) as brown solid. Yield: 0.70 g, 50.0%; MS (ESI) m/z 512.2[M+1]⁺.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (12)

To a solution of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(11, 0.70 g, 1.30 mmol) in methanol and water (3:1, 20 mL), lithiumhydroxide (0.32 g, 13.60 mmol) was added and the reaction was stirredfor 2 h at room temperature. After completion, the reaction mass wascooled to 0° C. and acidified with 1 M hydrochloric acid to pH ˜2-3. Theprecipitate was filtered and dried under vacuum to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (12) as white solid. Yield: 0.53 g, 77.3%; MS (ESI) m/z498.08[M+1]⁺.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(13)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (12, 0.53 g, 1.00 mmol) in dichloromethane (25 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.49 g, 3.10 mmol),hydroxybenzotriazole (0.48 g, 3.10 mmol) and N,N-diisopropylethylamine(0.82 g, 6.30 mmol) were added and the mixture was stirred for 5 min.Dimethylamine hydrochloride (0.43 g, 5.20 mmol) was then added at thesame temperature and the reaction was stirred for 28 h at roomtemperature. After completion, the reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by silica gel column chromatographyusing 60-70% ethyl acetate in hexanes as eluent. The desired fractionswere concentrated to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(13) as white solid. Yield: 0.38 g, 68%; MS (ESI) m/z 525.24[M+1]⁺.

Synthesis of(4bS,5R,6R,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 64F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(13, 0.38 g, 0.73 mmol) in N,N-dimethylformamide (5.0 mL), zinc cyanide(0.51 g, 4.40 mmol) and zinc dust (0.005 g, 0.08 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (8 mg, 0.0014 mmol) andtris(dibenzylideneacetone)dipalladium (19 mg, 0.021 mmol) were added tothe reaction, degassed for additional 5 min and heated the mixture at140° C. for 16 h. After completion, the reaction mass was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by silica gel column chromatographyusing 2-3% methanol in dichloromethane as eluent. The desired fractionswere concentrated to afford rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(rac-Cpd. No. 64F) as white solid. The enantiomers were separated bychiral preparative HPLC [chiralpak IB (4.6×250) mm]. Yield: 0.169 g, 49%(racemic mixture) Peak 1 (31 mg), [α]_(D) +89.6° (c 0.1, CHCl₃),R_(t)=7.796 min, ee>99% ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 1H), 8.00(s, 1H), 7.48 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 7.02 (t, J=7.3Hz, 2H), 6.94 (m, 3H), 5.8 (s, 1H), 5.16 (d, J=5.4 Hz, 1H), 4.76 (t,J=5.2 Hz, 1H), 4.49 (d, J=13.4 Hz, 1H), 4.25 (dd, J=13.4, 5.1 Hz, 1H),3.87 (s, 3H), 3.29 (s, 3H), 2.77 (s, 3H); MS (ESI) r/z 472.43 [M+1]+;Purity: 99.32% Peak-2 (Cpd. No. 64F, 26 mg), [α]_(D) −89.5° (c 0.1,CHCl₃), R_(t)=10.192 min, ee>99% ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (s,1H), 8.00 (s, 1H), 7.48 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 7.02(t, J=7.3 Hz, 2H), 6.94 (m, 3H), 5.8 (s, 1H), 5.16 (d, J=5.4 Hz, 1H),4.76 (t, J=5.2 Hz, 1H), 4.49 (d, J=13.4 Hz, 1H), 4.25 (dd, J=13.4, 5.1Hz, 1H), 3.87 (s, 3H), 3.29 (s, 3H), 2.77 (s, 3H); MS (ESI) r/z 472.43[M+1]+; Purity: 99.04%.

Example 65Rac-4-((4bS,5R,6S,7S,7aR)-6-(aminomethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 65F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(2)

To a suspension ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 2.50 g, 5.02 mmol) in dichloromethane (30 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g,10.03 mmol), 1-hydroxybenzotriazole (1.36 g, 10.03 mmol) andN,N-diisopropylethylamine (1.95 g, 15.05 mmol). The mixture was stirredat 0° C. for 5 min, then ammonium chloride (322 mg, 6.02 mmol) was addedand the mixture was stirred at 20° C. for 12 h. The mixture was dilutedwith water (20 mL) and extracted with dichloromethane (60 mL×2). Theorganic layer was dried and concentrated under reduced pressure to givea residue, which was purified by silica gel chromatography(dichloromethane: methanol=20:1 to 10:1) to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(2) as a light yellow solid. Yield: 2.00 g, 80%; MS (ESI) m/z 497.0[M+1]; ¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (s, 1H), 7.97 (s, 1H), 7.71 (s,1H), 7.22 (d, J=8.4 Hz, 1H), 7.07-6.99 (m, 8H), 5.69 (s, 1H), 5.17 (d,J=4.0 Hz, 1H), 4.60 (t, J=4.4 Hz, 1H), 4.30 (d, J=14.0 Hz, 1H),3.91-3.90 (m, 1H), 3.87 (s, 3H).

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-6-(aminomethyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (3)

To a suspension ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(2, 2.00 g, 4.02 mmol) in tetrahydrofuran (40 mL) was added boranedimethyl sulfide complex (10 M, 4.02 mL) at 0° C. and the mixture washeated to 60° C. for 0.5 h. The mixture was cooled to 0° C., quenchedwith methanol (20 mL) and concentrated under reduced pressure to give acrude product, which was triturated in hexane/dichloromethane (10/1, 20mL) and filtered off solid to affordrac-(4bS,5R,6S,7S,7aR)-6-(aminomethyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3) as a white solid. Yield: 1.20 g, 62%; MS (ESI) m/z 483.1[M+1]⁺.

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-6-(aminomethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 65F)

A mixture ofrac-(4bS,5R,6S,7S,7aR)-6-(aminomethyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3, 500 mg, 1.03 mmol), zinc powder (67 mg, 1.03 mmol), zinc cyanide(1.21 g, 10.34 mmol), tris(dibenzylideneacetone)dipalladium (95 mg,103.4 umol) and 1,1′-bis(diphenylphosphino)ferrocene (57 mg, 103.4 umol)in dimethyl sulfoxide (4 mL) was stirred at 130° C. under nitrogen atmicrowave irradiate (150 Psi, 40 W) for 1 h. The reaction mixture waspurified by silica gel chromatography (dichloromethane/methanol=20:1 to10:1) to give the product, which was further purified by prep-HPLC(column: Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05%ammonia hydroxide v/v)-acetonitrile]; B %: 40%-70%, 10 min) to affordrac-4-((4bS,5R,6S,7S,7aR)-6-(aminomethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 65F) as a light yellow solid. Yield: 22 mg, 5%; MS (ESI) m/z430.1 [M+1]⁺; HPLC: 99.89%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (s, 1H),7.98 (s, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.08-7.04(m, 2H), 7.01-6.99 (m, 3H), 5.68 (s, 1H), 4.59 (d, J=4.4 Hz, 1H), 3.89(s, 3H), 3.77 (d, J=14.0 Hz, 1H), 3.06-2.90 (m, 1H), 2.67-2.60 (m, 2H).

Example 664-((4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 66F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 500 mg, 0.95 mmol) dissolved in tetrahydrofuran (3 mL) was addedborane dimethyl sulfide complex solution (10 M, 0.95 mL) at 0° C. andthe mixture was stirred at 25° C. for 30 min, then the mixture wasreflux at 60° C. for 2 h. TLC (dichloromethane/methanol=10:1) showedthere was no starting material. The reaction mixture was quenched withacetic acid (2 mL) at 0° C. and the mixture was reflux at 60° C. for 1h, LCMS showed there was desired product detected. The reaction mixturewas concentrated and the residue was diluted with water (30 mL). Theresulting mixture was extracted with ethyl acetate (10 mL×3). The waterphase was adjusted pH=7-8 with saturated sodium bicarbonate and thenextracted with ethyl acetate (10 mL×5). The combined organic layer wasdried over anhydrous sodium sulfate and concentrated in vacuum to affordthe productrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as a white solid. Yield: 400 mg, 79%; MS (ESI) m/z 510.8 [M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 66F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 150 mg, 0.29 mmol) dissolved in dimethyl sulfoxide (3 mL) was addedzinc (19 mg, 0.29 mmol), zinc cyanide (344 mg, 2.93 mmol) at 25° C. andthe reaction mixture was degassed with nitrogen for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (16 mg, 0.29 mmol) andtris(dibenzylideneacetone)dipalladium (17 mg, 0.029 mmol) was added andthe mixture was stirred in microwave (100 w, 140° C., 150 psi) for 2 h.LCMS showed desired product. The reaction mixture was filtered and thefiltrate was concentrated in vacuum. The crude was purified by column(dichloromethane/methanol=10:1) to affordrac-4-((4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas a brown solid. Yield: 120 mg, 89%. The enantiomers were separated bySFC column: AD (250 mm×30 mm, 10 um); mobile phase: [0.1% ammoniumhydroxide/isopropanl]; B %: 40%-40%, 4 min: 90 min). Peak 1 (Cpd. No.66F, 17 mg), [α]_(D) +2.988° (c 0.08, CHCl₃), [α]_(D) +20.078° (c 0.5,methanol); Rt=3.155 min, ee>98%; MS (ESI) m/z 458.2 [M+1]⁺; HPLC:98.46%; 1H NMR (400 MHz, CD₃OD) δ 8.03 (s, 1H), 7.96 (s, 1H), 7.49 (d,J=8.8 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.09-6.99 (m, 5H), 4.75 (d, J=4.8Hz, 1H), 3.99 (s, 3H), 3.83 (d, J=14.4 Hz, 1H), 3.26-3.24 (m, 1H),2.86-2.80 (m, 1H), 2.38 (s, 6H), 2.26-2.23 (m, 1H); Peak 2 (21 mg);[α]_(D) −7.394° (c 0.08, CHCl₃), [α]_(D) −11.907° (c 0.5, methanol);Rt=3.607 min, ee>98%; MS (ESI) m/z 458.2 [M+1]⁺; HPLC: 97.65%; ¹H NMR(400 MHz, CD₃OD) δ 8.03 (s, 1H), 7.96 (s, 1H), 7.49 (d, J=8.8 Hz, 2H),7.42 (d, J=8.4 Hz, 2H), 7.09-6.99 (m, 5H), 4.75 (d, J=4.8 Hz, 1H), 3.99(s, 3H), 3.83 (d, J=14.4 Hz, 1H), 3.28-3.24 (m, 1H), 2.86-2.80 (m, 1H),2.47 (s, 6H), 2.25-2.21 (m, 1H).

Example 674-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(piperazin-1-ylmethyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 67F)

Synthesis of rac-tert-butyl4-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carbonyl)piperazine-1-carboxylate(3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.50 g, 3.01 mmol) in dichloromethane (10 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbod-iimide hydrogen chloride (1.20g, 6.02 mmol), 1-hydroxybenzotriazole (813 mg, 6.02 mmol) andN,N-diisopropylethylamine (1.60 g, 12.04 mmol, 2.1 mL) at 0° C. and themixture was stirred at 0° C. for 30 min. Then tert-butylpiperazine-1-carboxylate (617 mg, 3.31 mmol) was added and the mixturewas stirred at 25° C. for 12 h. LCMS showed there was desired productdetected. The reaction mixture was diluted with dichloromethane (100 mL)and washed with water (100 mL×3). The resulting organic layer was driedover anhydrous sodium sulfate and concentrated in vacuum. The crude waspurified by column (dichloromethane/methanol=20:1) to afford the productrac-tert-butyl4-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carbonyl)piperazine-1-carboxylate(3) as a yellow solid. Yield: 1.00 g, 47%; MS (ESI) m/z 668.1 [M+1]⁺.

Synthesis of rac-tert-butyl4-(((4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methyl)piperazine-1-carboxylate(4)

To a solution of rac-tert-butyl4-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carbonyl)piperazine-1-carboxylate(3., 1.00 g, 1.50 mmol) dissolved in tetrahydrofuran (10 mL) was addedborane dimethyl sulfide complex solution (10 M, 1.50 mL) at 0° C. andthe mixture was stirred at 25° C. for 30 min, then the mixture wasreflux at 60° C. for 2 h. LCMS showed there was no starting materialleft. The reaction mixture was quenched with acetic acid (3 mL) at 0° C.and the mixture was reflux at 60° C. for 1 h. The reaction mixture wasconcentrated, washed with petroleum/ethyl acetate=2:1 (20 mL) andfiltered. The filter cake was diluted with water (30 mL) and extractedwith ethyl acetate (10 mL×2). The water phase was adjusted pH=7-8 withsaturated sodium bicarbonate and then extracted with ethyl acetate (20mL×3). The combined organic phase was dried with anhydrous sodiumsulfate and concentrated in vacuum. The crude was purified by column(dichloromethane/methanol=20:1) to afford the product rac-tert-butyl4-(((4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methyl)piperazine-1-carboxylate(4) as a white solid. Yield: 500 mg, 49%; MS (ESI) m/z 654.4 [M+1]+.

Synthesis of tert-butyl4-(((4bS,5R,6S,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methyl)piperazine-1-carboxylate(5)

To a solution of rac-tert-butyl4-(((4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methyl)piperazine-1-carboxylate(4,250 mg, 0.38 mmol) dissolved in dimethyl sulfoxide (3 mL) was added zinc(25 mg, 0.38 mmol), zinc cyanide (180 mg,1.53 mmol) at 25° C. and thereaction mixture was degassed with nitrogen for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (21 mg, 0.038 mmol) andtris(dibenzylideneacetone)dipalladium (22 mg, 38.31 umol) were added andthe mixture was stirred in microwave (100 w, 140° C., 150 psi) for 2 h.LCMS showed there was desired product detected. The reaction mixture wasfiltered and the filtrate was concentrated in vacuum. The crude waspurified by column (dichloromethane/methanol=50:1) to affordrac-tert-butyl4-(((4bS,5R,6S,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methyl)piperazine-1-carboxylateas a brown solid. Yield: 75 mg, crude. The enantiomers were separated bySFC column: OD (250 mm×30 mm, 10 um); mobile phase: [0.1% NH₃H₂O,methanol]; B %: 25%-25%, 4.3 min; 200 minmin). Peak 1 (5, 16 mg), MS(ESI) m/z 599.3[M+1]⁺; Peak 2 (19 mg); MS (ESI) m/z 599.3 [M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(piperazin-1-ylmethyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 67F)

To a solution of tert-butyl4-(((4bS,5R,6S,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methyl)piperazine-1-carboxylate(5,65 mg, 0.11 mmol) in acetonitrile (1 mL) was added trifluoroacetic acid(112 mg, 0.65 mmol) at 25° C. The mixture was stirred at 25° C. for 1 h.LCMS showed desired product. The reaction mixture was adjusted pH=7-8with saturated sodium bicarbonate. The crude was purified by prep-HPLC(column: Phenomenex Gemini C18 250×21.2 mm×5 um; mobile phase: [water(0.05% ammonia hydroxide v/v)-acetonitrile]; B %: 23%-53%,12 min) toafford product4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(piperazin-1-ylmethyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 67F). Yield: 20 mg, 36%. [α]_(D) −5.430° (c 0.08, CHCl₃);Rt=3.515 min, ee>99%; MS (ESI) m/z 499.2 [M+1]⁺; HPLC: 97.40%; ¹H NMR(400 MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.96 (s, 1H), 7.48 (d, J=8.8 Hz, 2H),7.37 (d, J=8.4 Hz, 2H), 7.07-7.06 (m, 2H), 7.02-6.88 (m, 3H), 5.74 (brs,1H), 5.15 (brs, 1H), 4.50 (d, J=3.6 Hz, 1H), 3.88 (s, 3H), 3.80 (d,J=14.0 Hz, 1H), 3.35-3.27 (m, 1H), 2.72-2.70 (m, 4H), 2.70-2.68 (m, 2H),2.26-2.23 (m, 2H), 2.06 (dd, J=12.4 Hz, 2.0 Hz, 1H).

Example 68Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((4-methylpiperazin-1-yl)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 68F)

Synthesis ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4-methylpiperazin-1-yl)methanone(3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 2.50 g, 5.02 mmol) in dichloromethane (30 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g,10.03 mmol), 1-hydroxybenzotriazole (1.36 g, 10.03 mmol) andN,N-diisopropylethylamine (1.95 g, 15.05 mmol) at 0° C. The mixture wasstirred at 0° C. for 0.5 h. Then 1-methylpiperazine (2, 553 mg, 5.52mmol, 0.61 mL) was added. The mixture was stirred at 20° C. for 11.5 h.The mixture was diluted with water (50 mL) and extracted withdichloromethane (50 mL×3). The combined organic layer was washed withbrine (50 mL), dried over anhydrous sodium sulphate and concentrated.The residue was purified by column chromatography(dichloromethane/methanol=20:1 to 10:1) to affordrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4-methylpiperazin-1-yl)methanone(3) as a white solid. Yield: 2.60 g, 89%; MS (ESI) m/z 580.1 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 8.10 (s, 1H), 7.99 (s, 1H), 7.20 (d, J=8.8 Hz,2H), 7.11-7.01 (m, 4H), 6.99-6.89 (m, 3H), 5.72 (s, 1H), 5.17 (d, J=5.2Hz, 1H), 4.68 (t, J=5.2 Hz, 1H), 4.47 (d, J=13.6 Hz, 1H), 4.21 (dd,J=13.6 Hz, 5.2 Hz, 1H), 3.95-3.85 (m, 1H), 3.88 (s, 3H), 3.72-3.62 (m,1H), 3.55-3.45 (m, 1H), 3.32-3.24 (m, 1H), 2.62-2.53 (m, 1H), 2.44-2.31(m, 2H), 2.23 (s, 3H), 2.16-2.06 (m, 1H).

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((4-methylpiperazin-1-yl)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4)

To a solution ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4-methylpiperazin-1-yl)methanone(3, 2.60 g, 4.48 mmol) in tetrahydrofuran (30 mL) was added boranedimethyl sulfide complex (10 M, 4.48 mL) at 0° C. The mixture wasstirred at 0° C. for 0.5 h. Then the mixture was warmed to 70° C. andstirred at 70° C. for 1 h. The mixture was quenched with acetic acid (9mL) and then stirred at 70° C. for 1 h. The mixture was concentrated andwater (20 mL) was added. The mixture was washed with methyl t-butylether (30 mL×3). The aqueous layer was adjusted to pH=8 with saturatedsodium bicarbonate, extracted with ethyl acetate (50 mL×3). The combinedorganic layer was dried over sodium sulphate and concentrated to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((4-methylpiperazin-1-yl)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as a white solid. Yield: 2.00 g, 79%; MS (ESI) m/z 566.0 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 8.02 (s, 1H), 7.95 (s, 1H), 7.21 (d, J=8.8 Hz,2H), 7.14-7.06 (m, 4H), 7.03-6.97 (m, 3H), 6.53 (s, 1H), 5.62 (s, 1H),4.48 (d, J=4.0 Hz, 1H), 3.88 (s, 3H), 3.74 (d, J=14.0 Hz, 1H), 3.19-3.15(m, 1H), 2.62-2.55 (m, 2H), 2.46-2.26 (m, 6H), 2.19 (s, 3H), 2.08-2.04(m, 1H).

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((4-methylpiperazin-1-yl)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 68F)

A solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((4-methylpiperazin-1-yl)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 500 mg, 0.88 mmol), 1,1′-bis(diphenylphosphino)ferrocene (49 mg,0.088 mmol), tris(dibenzylideneacetone)dipalladium(0) (81 mg, 0.088mmol), zinc powder (58 mg, 0.88 mmol), zinc cyanide (518 mg, 4.41 mmol)in dimethyl sulfoxide (6 mL) was stirred under nitrogen at microwave(150 psi, 40 W) at 130° C. for 2 h. The mixture was filtered and thefiltrate was purified by column chromatography(dichloromethane/methanol=100:1 to 10:1) to give the product which wasthen further purified by Prep-HPLC (column: Phenomenex Gemini C18 250*50mm*10 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-acetonitrile];B %: 23%-48%,30 min,87% min) to affordrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((4-methylpiperazin-1-yl)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 68F) as a white solid. Yield: 142 mg, 31%; MS (ESI) m/z 513.2[M+1]⁺; HPLC:100%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.97 (s,1H), 7.48 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.08-7.05 (m, 2H),7.04-6.96 (m, 3H), 5.73 (s, 1H), 5.10 (d, J=2.4 Hz, 1H), 4.49 (s, 1H),3.88 (s, 3H), 3.80 (d, J=14.0 Hz, 1H), 3.24-3.21 (m, 1H), 2.65-2.55 (m,2H), 2.48-2.21 (m, 6H), 2.18 (s, 3H), 2.10-2.05 (m, 1H).

Example 69Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methylamino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 69F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 2.00 g, 4.01 mmol) in dichloromethane (10 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbod-iimide hydrogen chloride (1.54g, 8.03 mmol), 1-hydroxybenzotriazole (1.08 g, 8.03 mmol) andN,N-diisopropylethylamine (2.07 g, 16.05 mmol, 2.8 mL) at 0° C. and themixture was stirred at 0° C. for 30 minutes. Then methanamine (453.66mg, 4.82 mmol, 33% in methanol) was added and the mixture was stirred at25° C. for 12 h. LCMS showed there was desired product detected. Thereaction mixture was diluted with dichloromethane (20 mL) and washedwith water (60 mL×3). The organic phase was dried over anhydrous sodiumsulfate and concentrated in vacuum. The crude was purified by columnchromatography (dichloromethane/methanol=20:1) to afford the productrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3) as a white solid. Yield: 1.86 g, 72% yield; MS (ESI) m/z 511.0[M+1]+.

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methylamino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3, 1.86 g, 3.64 mmol) in tetrahydrofuran (40 mL) was added boranedimethyl sulfide complex solution (10 M, 3.64 mL) at 0° C. and themixture was stirred at 25° C. for 30 min. Then the mixture was refluxedat 60° C. for 2 h. TLC (dichloromethane/methanol=10:1) showed there wasno starting material left. The reaction mixture was quenched with aceticacid (5 mL) at 0° C. and the mixture was reflux at 60° C. for 1 h. Thereaction mixture was concentrated and washed with petroleum/ethylacetate=2:1 (30 mL) and filtered. The filter-cake was diluted with water(30 mL) and extracted with ethyl acetate (10 mL×2). The water phase wasadjusted pH=7-8 with saturated sodium bicarbonate and then extractedwith ethyl acetate (20 mL×3). The combined organic phase was dried overanhydrous sodium sulfate and concentrated in vacuum to afford theproductrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methylamino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as a white solid. Yield: 1.45 g, 69%; MS (ESI) m/z 497.0 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.98 (s, 1H), 7.24 (d, J=8.8 Hz,2H), 7.13-7.08 (m, 4H), 7.03-7.01 (m, 3H), 5.68 (s, 1H), 4.59 (d, J=4.0Hz, 1H), 3.89 (s, 3H), 3.72 (d, J=14.4 Hz, 1H), 3.23-3.17 (m, 3H),2.81-2.78 (m, 1H), 2.57-2.53 (m, 1H), 2.37 (s, 3H).

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methylamino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 69F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methylamino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 300 mg, 0.60 mmol) in dimethyl sulfoxide (3 mL) was added zinccyanide (283 mg, 2.41 mmol), zinc (79 mg, 1.21 mmol) at 25° C. and thereaction mixture was degassed with nitrogen for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (67 mg, 0.12 mmol) andtris(dibenzylideneacetone)dipalladium (110 mg, 0.12 mmol) was added andthe mixture was stirred in microwave (100 w, 140° C., 150 psi) for 2 h.LCMS showed desired product. The reaction mixture was filtered and thefiltrate was concentrated in vacuum. The crude was purified by columnchromatography (dichloromethane/methanol=10:1), monitored by LCMS. Thenthe crude was purified by Prep-HPLC (Phenomenex Gemini C18 250×50 mm×10um; mobile phase: [water (0.05% ammonia hydroxide v/v)−acetonitrile]; B%: 37%-62%, 30 min, 69% min) to afford the productrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methylamino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 69F) as a white solid. Yield: 99 mg, 37%; MS (ESI) m/z 444.2[M+1]⁺; HPLC: 99.81%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.98 (s,1H), 7.49 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.09-7.05 (m, 2H),7.01-6.99 (m, 3H), 5.73 (s, 1H), 4.56 (d, J=3.6 Hz, 1H), 3.89 (s, 3H),3.82 (d, J=14.0 Hz, 1H), 3.20-3.14 (m, 1H), 2.69-2.66 (m, 1H), 2.27 (s,3H).

Example 70Rac-4-((4bS,5R,6S,7S,7aR)-6-((ethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)cyclohexa-1,3-diene-1-carbonitrile(Cpd. No. 70F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-ethyl-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 2.00 g, 4.01 mmol) in dichloromethane (10 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.54 g,8.02 mmol), 1-hydroxybenzotriazole (1.08 g, 8.02 mmol) andN,N-diisopropylethylamine (2.07 g, 16.04 mmol, 2.8 mL) and the mixturewas stirred at 0° C. for 30 min. Then ethanamine (217 mg, 4.81 mmol) wasadded and the mixture was stirred at 25° C. for 12 h. LCMS showed therewas desired product detected. The reaction mixture was diluted withdichloromethane (30 mL) and washed with water (100 mL×3). The organicphase was dried over anhydrous sodium sulfate and concentrated invacuum. The crude was purified by column chromatography(dichloromethane/methanol=20:1) to afford the productrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-ethyl-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3) as a white solid. Yield: 1.7 g, 78%; MS (ESI) m/z 525.0 [M+1]⁺.

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((ethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-ethyl-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3, 1.70 g, 3.24 mmol) in tetrahydrofuran (10 mL) was added boranedimethyl sulfide complex solution (10 M, 3.24 mL) at 0° C. and themixture was stirred at 25° C. for 30 min. Then the mixture was reflux at60° C. for 2 h. TLC (dichloromethane/methanol=10:1) showed there was nostarting material left. The reaction mixture was quenched with aceticacid (5 mL) at 0° C. and the mixture was reflux at 60° C. for 1 h. Thereaction mixture was concentrated, washed with petroleum/ethylacetate=2:1 (30 mL) and filtered. The filter-cake was diluted with water(30 mL) and extracted with ethyl acetate (10 mL×2). The aqueous layerwas adjusted pH=7-8 with saturated sodium bicarbonate, extracted withethyl acetate (20 mL×3). The combined organic layer was dried overanhydrous sodium sulfate and concentrated in vacuum to afford theproductrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((ethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as a yellow solid. Yield: 1.20 g, 69%; MS (ESI) m/z 511.0 [M+1]⁺.

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-6-((ethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)cyclohexa-1,3-diene-1-carbonitrile(Cpd. No. 70F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((ethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 500 mg, 0.98 mmol) in dimethyl sulfoxide (2 mL) was added zinccyanide (459 mg, 3.91 mmol), zinc (64 mg, 0.98 mmol) and the reactionmixture was degassed with nitrogen for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (54 mg, 0.098 mmol) andtris(dibenzylideneacetone)dipalladium (56 mg, 0.098 mmol) was added andthe mixture was stirred in microwave (100 w, 140° C., 150 psi) for 2 h.LCMS showed there was desired product detected. The reaction mixture wasfiltered and the filtrate was concentrated in vacuum. The residue waspurified by column chromatography (dichloromethane/methanol=10:1) togive the crude which was further purified by Prep-HPLC (PhenomenexGemini C18 250×50 mm×10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)−acetonitrile]; B %: 37%-62%, 30 min, 69% min) to affordthe productrac-4-((4bS,5R,6S,7S,7aR)-6-((ethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)cyclohexa-1,3-diene-1-carbonitrile(Cpd. No. 70F) as a white solid. Yield: 174 mg, 38%; MS (ESI) m/z 458.2[M+1]⁺; HPLC: 97.93%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.98 (s,1H), 7.49 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.10-7.05 (m, 2H),7.01-6.88 (m, 3H), 5.68 (s, 1H), 4.55 (d, J=4.4 Hz, 1H), 3.89 (s, 3H),3.83 (d, J=14.4 Hz, 1H), 3.17-3.13 (m, 1H), 2.55-2.53 (m, 1H), 2.51-2.50(m, 1H), 2.49-2.46 (m, 1H), 0.97 (t, J=7.2 Hz, 3H).

Example 71Rac-4-((4bS,5R,6S,7S,7aR)-6-(azetidin-1-ylmethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 71F)

Synthesis ofrac-azetidin-1-yl((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(3)

A mixture ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 3.00 g, 6.02 mmol), 1-hydroxybenzotriazole (3.25 g, 24.1 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbod-iimide hydrogen chloride (2.31g, 12.0 mmol) and N,N-diisopropylethylamine (1.56 g, 12.0 mmol, 2.1 mL)in dichloromethane (40 mL) was stirred at 0° C. for 15 min and 25° C.for 30 min. Then azetidine (844 mg, 9.03 mmol, hydrogen chloride salt)was added and the mixture was stirred at 25° C. for 2 h. The mixture wasdiluted with water (40 mL), extracted with dichloromethane (40 mL×3).The combined extracts were washed with water (40 mL×2), brine (40 mL),evaporated in vacuo to get crude product. Chromatograph column(methanol/dichloromethane from 0% to 5%) gaverac-azetidin-1-yl((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(3) as a yellow solid. Yield: 2.50 g, 76%; MS(ESI+) m/z 537.0 [M+1]⁺; ¹HNMR (DMSO-d₆, 400 MHz) δ 8.09 (s, 1H), 7.99 (s, 1H), 7.20 (d, J=8.8 Hz,2H), 7.08-7.03 (m, 4H), 6.94-6.91 (m, 3H), 5.70 (s, 2H), 5.15 (d, J=5.2Hz, 1H), 4.66 (t, J=5.2 Hz, 1H), 4.54-4.50 (m, 1H), 4.39-4.35 (m, 2H),3.88 (s, 3H), 3.88-3.80 (m, 3H), 2.33-2.19 (m, 2H).

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-6-(azetidin-1-ylmethyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4)

To a mixture ofrac-azetidin-1-yl((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(3, 1.50 g, 2.79 mmol) in tetrahydrofuran (20 mL) was addedborane-methyl sulfide complex (10 M, 2.8 mL) drop-wise at 0° C. for 15min and the mixture was stirred at 60° C. for 4 h. The desired productcan be detected and no starting material by TLC. The mixture was cooledto 0° C., quenched with acetic acid (6 mL) drop-wise and stirred at 25°C. for 0.5 h and 60° C. for 1 h. The resulting solution was concentratedunder reduced pressure to give the crude product. The crude product wasdissolved in water (40 mL), extracted with methyl tert-butyl ether (40mL×2). The water phase was adjusted pH=8 with sodium bicarbonate(solid), extracted with ethyl acetate (40 mL×3). The combined extractswere washed with water (40 mL×2), brine (40 mL), evaporated in vacuo toaffordrac-(4bS,5R,6S,7S,7aR)-6-(azetidin-1-ylmethyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as a white solid. Yield: 1.30 g, 88%; MS (ESI+) m/z 525.1 [M+1]⁺. ¹HNMR (DMSO-d₆, 400 MHz) δ 8.01 (s, 1H), 7.95 (s, 1H), 7.21 (d, J=8.8 Hz,2H), 7.12-7.08 (m, 4H), 7.03-6.96 (m, 3H), 5.60 (s, 1H), 4.46 (d, J=3.6Hz, 1H), 3.88 (s, 3H), 3.77-3.72 (m, 1H), 3.11-3.05 (m, 4H), 2.95-2.85(m, 1H), 2.67-2.51 (m, 2H), 1.93-1.88 (m, 2H).

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-6-(azetidin-1-ylmethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 71F)

Rac-(4bS,5R,6S,7S,7aR)-6-(azetidin-1-ylmethyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 300 mg, 573 umol), 1,1′-Bis(diphenylphosphino)ferrocene (64 mg, 114umol), zinc (38 mg, 573 umol), zinc cyanide (673 mg, 5.73 mmol) andtris(dibenzylideneacetone)dipalladium (105 mg, 115 umol) in dimethylsulphoxide (3 mL) was stirred at microwave (100° C., 140 W) for 2.5 hunder nitrogen. The desired product can be detected by LCMS. The mixturewas directly purified by column chromatography (methanol/dichloromethanefrom 0% to 10%) to give the crude product (100 mg as a brown oil). Thecrude was purified by Prep-HPLC (column: Phenomenex Gemini C18 250*21.2mm*5 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-acetonitrile]; B %: 32%-62%, 12 min) and lyophilized to giverac-4-((4bS,5R,6S,7S,7aR)-6-(azetidin-1-ylmethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 71F). Yield: 10 mg, 4%; MS (ESI+) m/z 470.2 [M+1]⁺; HPLC:100%; ¹H NMR (DMSO-d₆, 400 MHz) δ 8.05 (s, 1H), 7.97 (s, 1H), 7.49 (d,J=8.4 Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 7.11-7.07 (m, 2H), 7.03-6.99 (m,3H), 5.72 (s, 1H), 5.66 (brs, 1H), 4.48 (d, J=4.0 Hz, 1H), 3.88 (s, 3H),3.82 (d, J=14.0 Hz, 1H), 3.14-3.08 (m, 4H), 2.95-2.85 (m, 1H), 2.70-2.60(m, 1H), 2.38-2.36 (m, 1H), 1.92 (t, J=6.8 Hz, 2H).

Example 72Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(pyrrolidin-1-ylmethyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 72F)

Synthesis ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(pyrrolidin-1-yl)methanone(3)

To a suspension ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 2.00 g, 4.01 mmol) in dichloromethane (30 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.54 g,8.02 mmol), 1-hydroxybenzotriazole (1.08 g, 8.02 mmol) andN,N-diisopropylethylamine (2.07 g, 16.04 mmol) at 0° C. After stirredfor 1 h at 25° C., pyrrolidine (570 mg, 8.02 mmol) was added and thereaction was stirred at 25° C. for 14 h. TLC(dichloromethane/methanol=20/1) indicated the R1 was consumed. Thereaction uspension was diluted with water (80 mL) and dichloromethane(80 mL). The insoluble was collected by filtration as the product aswhite solid. The suspension was extracted with dichloromethane (30 mL×3)and the combined organic layer was concentrated to give a residue. Theresidue was purified by column chromatography(dichloromethane/methanol=20/1) to afford the productrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(pyrrolidin-1-yl)methanone(3) as white solid. Yield: 2.2 g, 90%; MS (ESI) m/z 551.1 [M+1]+.

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(pyrrolidin-1-ylmethyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (4)

To a suspension ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(pyrrolidin-1-yl)methanone(3, 2.20 g, 3.99 mmol) in tetrahydrofuran (40 mL) was added boranedimethyl sulfide complex (10 M, 1.99 mL) dropwise at 25° C. After 10min, the suspension was heated at 65° C. for 3 h. LCMS indicated thereaction completed. The reaction was quenched by the addition of aceticacid (20 mL) dropwise at 25° C. and the resulting solution was stirredat 65° C. for 1 h. The solution was concentrated under reduced pressureand the residue was diluted with water (20 mL). It was extracted withmethyl t-butyl ether (20 mL×2) and the resulting aqueous layer wasneutralized by saturated aqueous sodium bicarbonate to pH=9. The aqueouslayer was extracted with dichloromethane (20 mL×3). The combined organiclayer was dried over anhydrous sodium sulfate, concentrated underreduced pressure to afford the desired productrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(pyrrolidin-1-ylmethyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as white solid. Yield: 1.2 g, 51.8%; MS (ESI) m/z 537.1 [M+1]+.

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(pyrrolidin-1-ylmethyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 72F)

A solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(pyrrolidin-1-ylmethyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 500 mg, 930 umol), 1,1′bis(diphenylphosphino)ferrocene (52 mg, 93umol), tris(dibenzylideneacetone)dipalladium(0) (85 mg, 93 umol), zincpowder (61 mg, 930 umol), zinc cyanide (546 mg, 4.65 mmol) in dimethylsulfoxide (2 mL) was stirred under nitrogen at microwave (150 psi, 40 W)at 140° C. for 2 h. The mixture was filtered and filtrate was purifiedby column chromatography (dichloromethane: methanol=100:1 to 10:1) toaffordrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(pyrrolidin-1-ylmethyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 72F) as a pink solid. Yield: 199 mg, 44%; MS (ESI) m/z 484.2[M+1]+; HPLC: 95.065%; 1H NMR (400 MHz, DMSO-d₆) δ 9.52 (brs, 1H), 8.10(s, 1H), 8.03 (s, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H),7.15-7.03 (m, 5H), 5.92 (s, 1H), 5.36 (d, J=5.6 Hz, 1H), 4.72 (t, J=5.6Hz, 1H), 3.91 (s, 3H), 3.82 (d, J=13.6 Hz, 2H), 3.70-3.59 (m, 1H),3.54-3.42 (m, 1H), 3.17-3.04 (m, 2H), 2.95-2.86 (m, 1H), 2.10-1.88 (m,4H).

Example 734-((4bS,5R,6S,7S,7aR)-6-((diethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 73F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N,N-diethyl-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.50 g, 3.01 mmol) in dichloromethane (10 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbod-iimide hydrogen chloride (1.15g, 6.02 mmol), 1-hydroxybenzotriazole (813 mg, 6.02 mmol) andN,N-diisopropylethylamine (2.33 g, 18.06 mmol, 3.15 mL) at 0° C. and themixture was stirred at 0° C. for 30 minutes. Then N-ethylethanamine (495mg, 4.51 mmol, hydrochloride) was added and the mixture was stirred at25° C. for 12 h. LCMS showed there was desired product detected. Thereaction mixture was washed with water (30 mL×3). The organic layer wasdried over anhydrous sodium sulfate and concentrated in vacuum to givethe crude. The crude was purified by column chromatography(dichloromethane: methanol=20:1) to afford the productrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N,N-diethyl-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3) as a yellow solid. Yield: 1.00 g, 54.82% yield; MS (ESI) m/z 555.1[M+1]⁺.

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((diethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N,N-diethyl-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3, 1.00 g, 1.81 mmol) dissolved in tetrahydrofuran (10 mL) was addedborane dimethyl sulfide complex solution (10 mol/L, 1.81 mL) at 0° C.and the mixture was stirred at 25° C. for 30 min. Then the mixture wasreflux at 60° C. for 2 h. LCMS showed there was no starting material.The reaction mixture was quenched with acetic acid (3 mL) at 0° C. andthe mixture was reflux at 60° C. for 1 h. LCMS showed there was desiredproduct detected. The reaction mixture was concentrated and the residuewas washed with petroleum: ethyl acetate=2:1 (30 mL) and filtered. Thefilter cake was diluted with water (30 mL) and extracted with ethylacetate (10 mL×2). The aqueous layer was adjusted pH=7-8 with saturatedsodium bicarbonate solution and then extracted with ethyl acetate (20mL×3). The combined organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuum to afford the productrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((diethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as a white solid. Yield: 620 mg, 56.35%; MS (ESI) m/z 539.1 [M+1]+.

Synthesis of4-((4bS,5R,6S,7S,7aR)-6-((diethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 73F)

A mixture ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((diethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 30 mg, 55.6 umol), zinc powder (4 mg, 55.6 umol),tris(dibenzylideneacetone)dipalladium(0) (5 mg, 5.56 umol),bis(diphenylphosphino)ferrocene (3 mg, 5.56 umol) and zinc cyanide (65mg, 556 umol) in dimethyl sulfoxide (1 mL) was stirred at 130° C. undernitrogen in microwave (150 Psi, 40 W) for 1 h. The reaction mixture wasdirectly purified by silica gel chromatography (dichloromethane:methanol=20:1 to 10:1) to give the product, which were separated bychiral Prep-HPLC (AD-3S_5_40_3.0 mL Column: Chiralpak AD-3 100×4.6 mmI.D, 3 um Mobile phase: 40% ethanol (0.05% DEA) in CO₂ Flow rate: 3.0mL/min AD-3S_4_5_40_3 mL; Column: Chiralpak AD-3 100×4.6 mm I.D, 3 umMobile phase: iso-propanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate:3 mL/min Wavelength: 220 nm) to afford two enantiomers. The twoenantiomers were further purified by Prep-HPLC (column: PhenomenexGemini C₁₈ 250×21.2 mm×5 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-acetonitrile]; B %: 41%-71%, 12 min) to give the two pureproducts4-((4bS,5R,6S,7S,7aR)-6-((diethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 73F); Peak 1 (Cpd. No. 73, 1.1 mg), Yield: 4.07%; [α]_(D)−13.228° (c 0.08, CHCl₃), R_(t)=0.562 min, ee=100%; MS (ESI) m/z 486.2[M+1]⁺; HPLC: 99.90%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.97 (s,1H), 7.49 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.09-7.05 (m, 2H),7.02-6.99 (m, 3H), 5.71 (s, 1H), 5.20 (s, 1H), 4.50 (d, J=3.2 Hz, 1H),3.88 (s, 3H), 3.84 (d, J=14.4 Hz, 1H), 3.20-3.16 (m, 1H), 2.62-2.52 (m,3H), 2.49-2.44 (m, 2H), 2.30-2.25 (m, 1H), 0.94 (t, J=7.2 Hz, 6H); Peak2 (Cpd. No. 73, 2.2 mg), Yield: 8.15%; [α]_(D) +10.096° (c 0.08, CHCl₃),+3.039° (c 0.08, methanol), R_(t)=1.317 min, ee=99.72%; MS (ESI) m/z486.2 [M+1]⁺; HPLC: 100%; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.05 (s, 1H),7.97 (s, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.09-7.05(m, 2H), 7.02-6.99 (m, 3H), 5.73 (s, 1H), 5.22 (s, 1H), 4.50 (s, 1H),3.88 (s, 3H), 3.84 (d, J=14.0 Hz, 1H), 3.31-3.25 (m, 1H), 2.62-2.58 (m,3H), 2.49-2.44 (m, 2H), 2.30-2.25 (m, 1H), 0.94 (t, J=7.2 Hz, 6H).

Example 74Rac-4-((4bS,5R,6S,7S,7aR)-6-((ethyl(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 74F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-ethyl-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3)

To a mixture ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 3.00 g, 6.02 mmol) in dichloromethane (45 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.31 g,12.04 mmol), 1-hydroxybenzotriazole (1.63 g, 12.04 mmol) andN,N-diisopropylethylamine (2.33 g, 18.06 mmol). The mixture was stirredat 0° C. for 10 min, then N-methylethanamine (427 mg, 7.22 mmol) wasadded and the mixture was stirred at 20° C. for 12 h. The mixture wasdiluted with dichloromethane (20 mL) and washed with water (20 mL×2).The organic layer was dried and concentrated under reduced pressure togive a residue, which was purified by silica gel chromatography(dichloromethane: methanol=50:1 to 10:1) to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-ethyl-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3) as a light yellow solid. Yield: 2.70 g, 83.15%; MS (ESI) m/z 539.0[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 1H), 7.99 (s, 1H),7.22-7.20 (m, 2H), 7.08-7.05 (m, 4H), 7.04-7.02 (m, 1H), 6.89-6.57 (m,2H), 5.69 (s, 1H), 5.11-5.08 (m, 1H), 4.75-4.71 (m, 1H), 4.49-4.41 (m,1H), 4.16-4.11 (m, 1H), 3.88 (s, 3H), 3.70-3.56 (m, 1H), 3.26-3.23 (m,4H), 1.30 (t, J=7.2 Hz, 1H), 0.95 (t, J=7.2 Hz, 2H).

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((ethyl(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-ethyl-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3, 2.70 g, 5.01 mmol) in tetrahydrofuran (50 mL) was added boranedimethyl sulfide complex (10 M, 5.0 mL) at 0° C. under the nitrogenatmosphere. The mixture was stirred at 0° C. for 30 min, then reflux at65° C. for 2 h. TLC (dichloromethane: methanol=10:1) showed the startingmaterial was consumed completely. The reaction mixture was cooled to 0°C. and quenched with acetic acid (10 mL). Then the mixture was stirredat 25° C. for 10 min and heated at 60° C. for 1 h. Removed solvent underreduce pressure, the residue was diluted with water (80 mL), washed withmethyl tertiary buthyl ether (40 mL×2). The water phase was adjusted pHto 8 with saturated sodium bicarbonate solution, extracted with ethylacetate (50 mL×3). Combined the extracts, washed by brine (40 mL), driedover anhydrous sodium sulfate, filtrated and concentrated to giverac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((ethyl(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as a white solid. Yield: 1.20 g, 61%; MS (ESI) m/z: 527.0 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 8.02 (s, 1H), 7.95 (s, 1H), 7.22-7.20 (m, 2H),7.13-7.06 (m, 4H), 7.00-6.98 (m, 3H), 5.63 (s, 1H), 4.49 (d, J=4.0 Hz,1H), 3.88 (s, 3H), 3.75 (d, J=14.0 Hz, 1H), 3.14-3.11 (m, 1H), 2.50-2.49(m, 1H), 2.49-2.47 (m, 1H), 2.35-2.25 (m, 1H), 2.21 (s, 3H), 2.15-2.05(m, 1H), 0.95 (t, J=7.2 Hz, 3H).

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-6-((ethyl(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 74F)

To a mixture ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((ethyl(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 500 mg, 951.6 umol), tris(dibenzylideneacetone)dipalladium (87 mg,95.16 umol), 1,1′-bis(diphenylphosphino)ferrocene (53 mg, 95.16 umol),Zinc (62 mg, 951.6 umol), zinc cyanide (447 mg, 3.81 mmol) were taken upinto a microwave tube in dimethyl sulfoxide (5 mL) under nitrogen at 25°C. After addition, the sealed tube was heated at 130° C. for 2 h inmicrowave (40 W, 20 bar). The reaction mixture was purified by silicagel column chromatography (dichloromethane: methanol=20:1 to 10:1) togive the crude product, which was purification by trituration frommethanol (5 mL) to give pure productrac-4-((4bS,5R,6S,7S,7aR)-6-((ethyl(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 74F) as white solid. Yield: 138 mg, 30.5%; MS (ESI) m/z 472.2[M+1]⁺; HPLC: 99.23%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.97 (s,1H), 7.49 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H), 7.08-7.05 (m, 2H),7.02-7.00 (m, 3H), 5.73 (s, 1H), 5.17 (bs, 1H), 4.50 (s, 1H), 3.88 (s,3H), 3.82 (d, J=14.0 Hz, 1H), 2.60-2.57 (m, 1H), 2.49-2.47 (m, 1H),2.31-2.30 (m, 1H), 2.22 (s, 3H), 2.12-2.11 (m, 1H), 0.97 (t, J=7.2 Hz,3H).

Example 75Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxyethyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 75F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxyethyl)-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3)

To a suspension ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 2.00 g, 4.01 mmol) in dichloromethane (20 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.54 g,8.02 mmol), 1-hydroxybenzotriazole (1.08 g, 8.02 mmol) andN,N-diisopropylethylamine (2.07 g, 16.04 mmol) at 0° C. After stirredfor 1 h at 25° C., 2-(methylamino)ethanol (602 mg, 8.02 mmol) was addedand the reaction was stirred at 25° C. for 14 h. TLC(dichloromethane/methanol=20/1) indicated the starting material wasconsumed. The reaction suspension was diluted with water (80 mL) andextracted with dichloromethane (40 mL×3). The combined organic layer wasconcentrated to give a residue. The residue combined was purified bycolumn chromatography (dichloromethane/methanol=10/1) to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxyethyl)-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3) as white solid. Yield: 1.5 g, crude; MS (ESI) m/z 555.0 [M+1]+.

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-hydroxyethyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4)

To a suspension ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxyethyl)-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3, 2.00 g, 3.60 mmol) in tetrahydrofuran (40 mL) was added boranedimethyl sulfide complex (10 M, 1.80 mL) dropwise at 25° C. After 10min, the suspension was heated at 65° C. for 2 h. TLC(dichloromethane/methanol=10/1) indicated the reaction completed. Thereaction was quenched by the addition of acetic acid (20 mL) at 25° C.dropwise and then the solution was stirred at 65° C. for 1 hr. Thesolution was concentrated under reduced pressure and the residue wasdiluted with dichloromethane (40 mL) and then neutralized by saturatedaqueous sodium bicarbonate to pH=9. The organic layer was separated andthe aqueous layer was extracted with dichloromethane (20 mL). Thecombined organic layer was dried over sodium sulfate, concentrated underreduced pressure to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-hydroxyethyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as white solid. Yield: 1.8 g, crude; MS (ESI) m/z 541.1 [M+1]⁺.

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxyethyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 75F)

A mixture ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-hydroxyethyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 450 mg, 831 umol), zinc cyanide (390 mg, 3.32 mmol), zinc (54 mg,831 umol), tris(dibenzylideneacetone)dipalladium (76 mg, 83 umol) and1,1′-Bis(diphenylphosphino)ferrocene (46 mg, 83 umol) indimethylsulfoxide (5 mL) was stirred at 130° C. for 1.5 hr undernitrogen at microwave irradiation. The reaction was performed 2 batchesin parallel and work up together. LCMS indicated the reaction completedand the desired product was main peak. The reaction mixture was pouredonto silica gel in a column and eluted withdichloromethane˜dichloromethane/methanol=10/1 (0.1% ammonia) to give thecrude product which was further purified by prep-HPLC (column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-acetonitrile];B %: 33%-63%,10 min) to afford the pureproductrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxyethyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 75F) as white solid. Yield: 205 mg, 25%; MS (ESI) m/z 541.1[M+1]⁺; HPLC: 99.08%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.96 (s,1H), 7.49 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 7.09-6.99 (m, 5H),5.72 (s, 1H), 5.06 (brs, 1H), 4.54 (d, J=4.0 Hz, 1H), 4.49 (s, 1H), 3.88(s, 3H), 3.80 (s, J=14.0 Hz, 1H), 3.48-3.44 (m, 2H), 3.27-3.19 (m, 1H),2.60-2.53 (m, 2H), 2.31-2.27 (m, 4H), 2.14 (dd, J=12.4, 3.2 Hz, 1H).

Example 76Rac-4-((4bS,5R,6S,7S,7aR)-6-((benzyl(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 76F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-N-benzyl-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 2.5 g, 5.02 mmol) in dichloromethane (25 mL) was addedcarbodiimide hydrochloride (1.92 g, 10.04 mmol), hydroxybenzotriazole(1.36 g, 10.04 mmol) and diisopropylethylamine (2.60 g, 20.08 mmol) at0° C. and the mixture was stirred at 0° C. for 30 minutes. Then1-phenylethanamine (607.9 mg, 5.02 mmol) was added and the mixture wasstirred at 25° C. for 12 h. LCMS showed there was desired productdetected. The reaction mixture was diluted with dichloromethane (30 mL)and washed with water (100 mL×3). The organic phase was dried overanhydrous sodium sulfate and concentrated in vacuum to afford theproductrac-(4bS,5R,6R,7S,7aR)-N-benzyl-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3) as a white solid. Yield: 2.76 g, crude; MS (ESI) m/z 601.3 [M+1]⁺.

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-6-((benzyl(methyl)amino)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4)

To a suspension ofrac-(4bS,5R,6R,7S,7aR)-N-benzyl-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3, 2.70 g, 4.49 mmol) in tetrahydrofuran (40 mL) was added boranedimethyl sulfide complex (10 M, 3.59 mL) dropwise at 25° C. After 10min, the suspension was heated at 65° C. for 1 h. TLC(dichloromethane/methanol=10/1) indicated the reaction completed. Thereaction was quenched by the addition of acetic acid (20 mL) at 25° C.dropwise and then the solution was stirred at 65° C. for 1 hr. Thesolution was concentrated under reduced pressure and the residue wasdiluted with water (60 mL). The suspension was basified by solid sodiumcarbonate to pH=10. The mixture was extracted with dichloromethane (60mL×2). The combined organic layer was dried over anhydrous sodiumsulfate, concentrated under reduced pressure to afford the crude productrac-(4bS,5R,6S,7S,7aR)-6-((benzyl(methyl)amino)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as white solid. Yield: 2.30 g, crude; MS (ESI) m/z 587.2 [M+1]⁺.

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-6-((benzyl(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 76F)

A mixture ofrac-(4bS,5R,6S,7S,7aR)-6-((benzyl(methyl)amino)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 1.0 g, 1.70 mmol), zinc cyanide (800 mg, 6.81 mmol), zinc (111 mg,1.70 mmol), tris(dibenzylideneacetone)dipalladium (156 mg, 0.17 mmol)and 1,1′-Bis(diphenylphosphino)ferrocene (94 mg, 0.17 mmol) indimethylsulfoxide (10 mL) was stirred at 140° C. for 1.5 h undernitrogen at microwave (140° C., 1.5 h, 20 bar) irradiation. The reactionwas performed 2 batches in parallel and work up together. LCMS indicatedthe desired product was main peak. The reaction mixture was poured ontosilica gel in a column and eluted withdichloromethane˜dichloromethane/methanol=10/1 (0.5% ammonia) to give thecrude product which was purification again by prep-HPLC (column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)-acetonitrile];B %: 45%-70%,26 MIN; 83% min) to afford thepure productrac-4-((4bS,5R,6S,7S,7aR)-6-((benzyl(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 76F) as white solid. Yield: 270 mg, 15%; MS (ESI) m/z 534.2[M+1]⁺; HPLC: 99.79%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.99 (s,1H), 7.48 (d, J=8.4 Hz, 2H), 7.36-7.32 (m, 7H), 7.07-6.95 (m, 5H), 5.76(s, 1H), 5.12 (d, J=4.8 Hz, 1H), 4.61 (s, 1H), 3.91 (s, 3H), 3.79 (d,J=14.0 Hz, 1H), 3.64 (d, J=13.2 Hz, 1H), 3.42 (d, J=13.2 Hz, 1H),3.27-3.23 (m, 1H), 2.72-2.66 (m, 1H), 2.22-2.19 (m, 4H).

Example 77Rac-4-((4bS,5R,6S,7S,7aR)-6-((benzylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 77F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-N-benzyl-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 2.50 g, 5.02 mmol) in dichloromethane (30 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g,10.03 mmol), 1-hydroxybenzotriazole (1.36 g, 10.03 mmol) andN,N-diisopropylethylamine (1.95 g, 15.05 mmol) at 0° C. The mixture wasstirred at 0° C. for 0.5 h. Then phenylmethanamine (645.47 mg, 6.02mmol) was added. The mixture was stirred at 20° C. for 11.5 h. Themixture was diluted with water (50 mL) and extracted withdichloromethane (50 mL×3). The combined organic layer was washed withbrine (50 mL), dried over anhydrous sodium sulphate and concentrated.The residue was purified by column chromatography (dichloromethane:methanol=20:1 to 10:1) to affordrac-(4bS,5R,6R,7S,7aR)-N-benzyl-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3) as a white solid. Yield: 2.10 g, 71.21%; MS (ESI) m/z 587.0 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (t, J=6.0 Hz, 1H), 8.09 (s, 1H), 7.99(s, 1H), 7.27-7.18 (m, 5H), 7.15-6.98 (m, 9H), 5.72 (s, 1H), 5.17 (d,J=4.4 Hz, 1H), 4.63 (t, J=4.4 Hz, 1H), 4.41 (d, J=14.4 Hz, 1H), 4.32(dd, J=15.2 Hz, 6.0 Hz, 1H), 4.20 (dd, J=15.2 Hz, 5.2 Hz, 1H), 3.99 (dd,J=14.4 Hz, 4.8 Hz, 1H), 3.88 (s, 3H).

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-6-((benzylamino)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-N-benzyl-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3, 2.10 g, 3.57 mmol) in tetrahydrofuran (30 mL) was added boranedimethyl sulfide complex (10 M, 3.57 mL) at 0° C. The mixture wasstirred at 0° C. for 0.5 h. Then the mixture was warmed to 70° C. andstirred at 70° C. for 1 h. The mixture was quenched with acetic acid (9mL) and then stirred at 70° C. for 1 h. The mixture was concentrated.Water (20 mL) was added. The mixture was washed with methyl t-butylether (30 mL×3). The aqueous layer was adjusted to pH=8 with saturatedsodium bicarbonate, extracted with ethyl acetate (50 mL×3). The combinedorganic layer was dried over sodium sulphate and concentrated to affordrac-(4bS,5R,6S,7S,7aR)-6-((benzylamino)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as a white solid. Yield: 1.00 g, 48.78%; MS (ESI) m/z 573.1 [M+1]+.

Synthesisrac-4-((4bS,5R,6S,7S,7aR)-6-((benzylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 77F)

A solution ofrac-(4bS,5R,6S,7S,7aR)-6-((benzylamino)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 500 mg, 872 umol), 1,1′bis(diphenylphosphino)ferrocene (48 mg, 87umol), tris(dibenzylideneacetone)dipalladium(0) (80 mg, 87 umol), zincpowder (57 mg, 872 umol), zinc cyanide (512 mg, 4.36 mmol) in dimethylsulfoxide (6 mL) was stirred under nitrogen at microwave (150 psi, 40 W)at 130° C. for 2 h. The mixture was filtered and purified by columnchromatography (dichloromethane: methanol=100:1 to 10:1) to give theproduct, which was further purified by prep-HPLC (column: PhenomenexSynergi Max-RP 250*50 mm*10 um; mobile phase: [water (0.05% ammoniahydroxide v/v)−acetonitrile];B %: 40%-65%,26 MIN; 73% min) to affordrac-4-((4bS,5R,6S,7S,7aR)-6-((benzylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 77F) as a gray solid. Yield: 205 mg, 45.25%; MS (ESI) m/z520.5 [M+1]⁺; HPLC: 99.69%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (s, 1H),7.98 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.31-7.25(m, 4H), 7.23-7.17 (m, 1H), 7.07-6.92 (m, 5H), 5.69 (s, 1H), 5.41 (brs,1H), 4.59 (d, J=4.0 Hz, 1H), 3.89 (s, 3H), 3.79 (d, J=14.4 Hz, 1H), 3.68(s, 2H), 3.22-3.12 (m, 1H), 2.71-2.63 (m, 1H).

Example 78Rac-4-((5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(((pyridin-3-ylmethyl)amino)methyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 78F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-N-(pyridin-3-ylmethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3)

To a suspension ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 5.00 g, 10.03 mmol) in dichloromethane (50 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.85 g,20.06 mmol), hydroxybenzotriazole (2.71 g, 20.06 mmol) andN,N-diisopropylethylamine (5.19 g, 40.12 mmol) at 0° C. The mixture wasstirred at 30° C. for 30 min, then 3-pyridylmethanamine (1.08 g, 10.03mmol) was added at 30° C. and the mixture was stirred at 30° C. for 16h. The solution was poured into water (50 mL) and filtered. Thefilter-cake was washed with dichloromethane (20 mL×3) to afford thecrude product. The crude product was triturated with a mixture solutionof dichloromethane: methanol=10:1 (30 mL) to giverac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-N-(pyridin-3-ylmethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3) as a white solid. Yield: 4.50 g, 73%; MS (ESI) m/z 588.0 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 8.71 (t, J=6.0 Hz, 1H), 8.40 (d, J=2.8 Hz, 2H),8.09 (s, 1H), 7.99 (s, 1H), 7.50-7.45 (m, 1H), 7.25-7.22 (m, 3H),7.08-6.97 (m, 7H), 5.71 (s, 1H), 5.21 (d, J=4.8 Hz, 1H), 4.64 (t, J=4.4Hz 1H), 4.41 (d, J=14.4 Hz, 1H), 4.31-4.25 (m, 2H), 3.98-3.96 (m, 1H),3.88 (s, 3H).

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(((pyridin-3-ylmethyl)amino)methyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-N-(pyridin-3-ylmethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3, 4.50 g, 7.65 mmol) in tetrahydrofuran was added borane dimethylsulfide complex (10 M, 3.64 mL) at 0° C. The solution was stirred at 60°C. for 1 h, then quenched with acetic acid (3 mL) at 0° C. and thenheated at 60° C. for 1 hr. The reaction mixture was concentrated invacuum and diluted with water (100 mL) and washed with ethyl acetate (50mL×2). The water phase was adjusted pH=7-8 with saturated sodiumbicarbonate at 0° C. and then extracted with ethyl acetate (200 mL×3).The combined organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuum to giverac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(((pyridin-3-ylmethyl)amino)methyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as a white solid. Yield: 4.50 g, 99%; MS (ESI) m/z 576.0 [M+1]+.

Synthesis ofrac-4-((5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(((pyridin-3-ylmethyl)amino)methyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 78F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(((pyridin-3-ylmethyl)amino)methyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 1.30 g, 2.26 mmol) in dimethyl sulfoxide (10 mL) was added zinccyanide (1.06 g, 9.04 mmol), zinc (296 mg, 4.52 mmol),1,1′-Bis(diphenylphosphino)ferrocene (251 mg, 452.0 umol) andtris(dibenzylideneacetone)dipalladium (414 mg, 452.0 umol) under N₂. Thesealed tube was heated at 130° C. for 3 h under microwave (40 w, 20bar). The reaction solution was filtered. The filtrate was purified bycolumn (dichloromethane: methanol=50:1) to afford the crude product. Thecrude product was further purified by Prep-HPLC to affordrac-4-((5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(((pyridin-3-ylmethyl)amino)methyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 78F) as a white solid. Yield: 287 mg, 24.3%; MS (ESI) m/z521.2 [M+1]+; HPLC: 97.52%; 1H NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H),8.41 (d, J=4.4 Hz, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 7.75-7.70 (m, 1H),7.49 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.31-7.28 (m, 1H),7.05-6.94 (m, 5H), 5.70 (s, 1H), 5.34 (brs, 1H), 4.59 (d, J=4.0 Hz, 1H),3.89 (s, 3H), 3.78 (d, J=14.4 Hz, 1H), 3.71-3.68 (m, 2H), 3.19-3.15 (m,1H), 2.69-2.63 (m, 1H), 2.46-2.43 (m, 1H).

Example 79Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxyethyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 79F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxyethyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3)

To a suspension ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 2.43 g, 4.88 mmol) in dichloromethane (30 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.87 g,9.75 mmol), 1-hydroxybenzotriazole (1.32 g, 9.75 mmol) andN,N-diisopropylethylamine (3.15 g, 24.38 mmol) under nitrogen atmosphereat 0° C. After 10 min, 2-aminoethanol (358 mg, 5.86 mmol) was added andthe mixture was stirred at 25° C. for 12 h. The mixture was diluted withdichloromethane (20 mL) and washed with water (20 mL×2). The organiclayer was dried and concentrated under reduced pressure to give aresidue, which was purified by silica gel chromatography(dichloromethane: methanol=50:1 to 10:1) to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxyethyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3) as a white solid. Yield: 1.40 g, 52.78%; MS (ESI) m/z 543.0 [M+1]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (t, J=5.6 Hz, 1H), 8.08 (s, 1H), 7.98(s, 1H), 7.22 (d, J=8.4 Hz, 2H), 7.08-6.98 (m, 7H), 5.67 (s, 1H), 5.05(d, J=3.6 Hz, 1H), 4.66 (t, J=5.2 Hz, 1H), 4.57 (t, J=4.0 Hz, 1H), 4.34(d, J=14.0 Hz, 1H), 3.97-3.93 (m, 1H), 3.87 (s, 3H), 3.33-3.20 (m, 2H),3.11-3.07 (m, 2H).

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-hydroxyethyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxyethyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3, 1.40 g, 2.59 mmol) in tetrahydrofuran (30 mL) was added boranedimethyl sulfide complex (10 M, 2.6 mL) at 0° C. under the nitrogenatmosphere. The mixture was stirred at 0° C. for 30 minutes and thenreflux at 65° C. for 2 h. TLC (dichloromethane: methanol=10:1) showedthe starting material was consumed completed. The reaction mixture wascooled to 0° C. and quenched with acetic acid (10 mL). Then the mixturewas stirred at 25° C. for 10 minutes and heated at 60° C. for 1 hour.Removed solvents under reduce pressure, the residue was diluted by water(80 mL), extracted with methyl tertiary buthyl ether (40 mL×2). Thewater phase was adjusted pH to 8 with saturated sodium bicarbonatesolution, and then extracted with ethyl acetate (50 mL×3). Combined theextracts, washed by brine (40 mL), dried over anhydrous sodium sulfate,filtrated and concentrated to giverac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-hydroxyethyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as a white solid. Yield: 794 mg, 56.96%; MS (ESI) m/z: 529.1 [M+1]+.

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxyethyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 79F)

A mixture ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-hydroxyethyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 400 mg, 758.4 umol), tris(dibenzylideneacetone)Dipalladium (105 mg,113.8 umol), 1,1′-bis(diphenylphosphino)ferrocene (63 mg, 113.8 umol),Zinc (50 mg, 758.4 umol), zinc cyanide (356 mg, 192.6 mmol) were takeninto a microwave tube in DMSO (4 mL) under nitrogen atmosphere at 25° C.After addition, the sealed tube was heated at 135° C. for 2.5 h undermicrowave (40 W, 20 bar). The reaction mixture was purified by silicagel column chromatography (dichloromethane: methanol=20:1 to 10:1) togive the crude product, which was purification by trituration withmethanol (5 mL) to give pure productrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxyethyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 79F) as white solid. Yield: 76 mg, 20.97%; MS (ESI) m/z 474.2[M+1]⁺; HPLC: 99.19%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (s, 1H), 8.03 (s,1H), 7.56 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.13-7.04 (m, 4H),5.88 (s, 1H), 5.20 (s, 1H), 4.71 (d, J=4.0 Hz, 1H), 3.91 (s, 3H), 3.78(d, J=14.4 Hz, 1H), 3.70-3.60 (m, 2H), 3.07-2.99 (m, 3H), 2.74-2.67 (m,1H).

Example 80Rac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-2-isopropyl-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 80F)

Synthesis of (E)-1-(2-isopropylhydrazono)propan-2-one (3)

To a solution of isopropylhydrazine hydrochloride (1, 19.5 g, 177 mmol)in acetic acid (21.2 mL), 2-oxopropanal (2, 10.2 g, 141 mmol) was addedat 0° C. The reaction was stirred 16 h at room temperature. Aftercompletion, the reaction mixture was partitioned between saturatedaqueous sodium bicarbonate solution and ethyl acetate. The organic layerwas separated, dried over anhydrous sodium sulphate and concentratedunder reduced pressure to afford (E)-1-(2-isopropylhydrazono)propan-2-one (3) as orange solid. Yield: 13.0 g, 57%; MS (ESI) m/z poorionization.

Synthesis of 1-(4-hydroxy-1-isopropyl-1H-pyrazol-3-yl) ethan-1-one (5)

To a solution of (E)-1-(2-isopropylhydrazono) propan-2-one (3, 13.1 g,102 mmol) in water, oxalaldehyde (4, 5.93 g, 102 mmol) was added at roomtemperature. The reaction was stirred 3 h at room temperature. Aftercompletion, reaction mixture was diluted with dichloromethane and washedwith cold water. The organic layer was separated and dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure to get the crude. The crude was purified by silica gel (100-200mesh) column chromatography using 5% ethyl acetate in hexanes as eluent.The desired fractions were concentrated to afford1-(4-hydroxy-1-isopropyl-1H-pyrazol-3-yl) ethan-1-one (5) as lightyellow liquid. Yield: 3.5 g, 20%; MS (ESI) m/z 169 [M+1]⁺.

Synthesis of(E)-3-(4-bromophenyl)-1-(4-hydroxy-1-isopropyl-1H-pyrazol-3-yl)prop-2-en-1-one (6)

To a solution of 1-(4-hydroxy-1-isopropyl-1H-pyrazol-3-yl)ethan-1-one(5, 3.5 g, 20.8 mmol) in methanol (17.5 mL), sodium hydroxide (2.5 g,62.5 mmol) was added at room temperature followed by addition of4-bromobenzaldehyde (3.8 g, 20.8 mmol). The reaction mixture was heatedat 90° C. for 30 min. After completion, reaction mass was cooled to roomtemperature and the precipitated solid was filtered, washed with waterand dried under vacuum to afford of(E)-3-(4-bromophenyl)-1-(4-hydroxy-1-isopropyl-1H-pyrazol-3-yl)prop-2-en-1-one(6) as yellow solid. Yield: 6.5 g, 93%; MS (ESI) m/z 333 [M−1]⁻.

Synthesis5-(4-bromophenyl)-6-hydroxy-2-isopropylpyrano[3,2-c]pyrazol-7(2H)-one(7)

To a solution of(E)-3-(4-bromophenyl)-1-(4-hydroxy-1-isopropyl-1H-pyrazol-3-yl)prop-2-en-1-one(6, 5.0 g, 14.97 mmol) in ethanol (50 mL) and dichloromethane (50 mL),10% aqueous sodium hydroxide solution (41 mL, 104.3 mmol) was addedfollowed by addition of hydrogen peroxide (11.8 mL, 104.3 mmol, 30%) atroom temperature. The reaction mass was stirred for 2 h (exotherm wasobserved). After completion, reaction mass was cooled and neutralizedwith 6 M hydrogen chloride to pH ˜7 and dichloromethane was distilledoff. The precipitated solid was filtered and dried under vacuum toafford5-(4-bromophenyl)-6-hydroxy-2-isopropylpyrano[3,2-c]pyrazol-7(2H)-one(7) as off white solid. Yield: 3.50 g, 67%; MS (ESI) m/z 347.24[M−1]⁻.

Synthesis of rac-methyl(6S,7S,8R)-5-(4-bromophenyl)-8-hydroxy-2-isopropyl-9-oxo-6-phenyl-5,6,7,8-tetrahydro-2H-5,8-methanooxepino[3,2-c]pyrazole-7-carboxylate(9&9a)

A solution of5-(4-bromophenyl)-6-hydroxy-2-isopropylpyrano[3,2-c]pyrazol-7(2H)-one(7, 4.1 g, 11.78 mmol) and methyl cinnamate (8, 19.0 g, 117.8 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedfor 12 h under 400 watts UV light. After completion, the solvent wasremoved under reduced pressure. The crude was purified by Combi-flash(40 g, RediSep column) using 5% methanol in dichloromethane as eluent.The desired fractions were concentrated under reduced pressure to affordrac-methyl(6S,7S,8R)-5-(4-bromophenyl)-8-hydroxy-2-isopropyl-9-oxo-6-phenyl-5,6,7,8-tetrahydro-2H-5,8-methanooxepino[3,2-c]pyrazole-7-carboxylate(9&9a). Yield: 4.0 g, crude.

Synthesis rac-methyl(4aR,5S,6R,7aR)-4a-(4-bromophenyl)-7a-hydroxy-2-isopropyl-7-oxo-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate (10)

The crude rac-methyl(6S,7S,8R)-5-(4-bromophenyl)-8-hydroxy-2-isopropyl-9-oxo-6-phenyl-5,6,7,8-tetrahydro-2H-5,8-methanooxepino[3,2-c]pyrazole-7-carboxylate(9a, 4.0 g) was suspended in methanol (100 mL) and treated with sodiummethoxide (25% in methanol, 40 mL) and heated the mixture to 80° C. for3 h. After completion, the solvent was removed under reduced pressure,diluted the mixture with ammonium chloride solution and extracted withethyl acetate. The organic phase was separated, dried over anhydroussodium sulphate and concentrated under reduced pressure to affordrac-methyl(4aR,5S,6R,7aR)-4a-(4-bromophenyl)-7a-hydroxy-2-isopropyl-7-oxo-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(10). Yield: 4.0 g, crude.

Synthesis rac-methyl (4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-isopropyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate (11)

To a solution of sodium triacetoxyborohydride (10.0 g, 47.05 mmol),rac-methyl(4aR,5S,6R,7aR)-4a-(4-bromophenyl)-7a-hydroxy-2-isopropyl-7-oxo-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(10, 4.0 g, 7.84 mmol) in acetonitrile (40 mL), acetic acid (4.7 mL,78.4 mmol) was added. The resulting mixture was stirred for 12 h at roomtemperature. After completion, reaction mixture was partitioned betweensaturated aqueous sodium bicarbonate solution and ethyl acetate. Theorganic layer was separated, dried over anhydrous sodium sulphate andconcentrated under reduced pressure to get the crude. The crude waspurified by Combi-flash (40 g, RediSep column) using 2% methanol indichloromethane as eluent. The desired fractions were concentrated toafford rac-methyl(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-isopropyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(11) as off white solid. Yield: 1.0 g, 25%; MS (ESI) m/z 511.51[M−1]⁻.

Synthesis ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-isopropyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylicacid (12)

To a solution of rac-methyl(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-isopropyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(11, 1.0 g, 2.0 mmol) in methanol:water (3:1, 16 mL), lithium hydroxide(0.964 g, 40.16 mmol) was added and the reaction was stirred for 2 h atroom temperature. After completion, methanol was distilled off, thereaction mass was cooled to 0° C. and acidified with 1 M hydrogenchloride to pH ˜6. The precipitated solid was filtered and dried undervacuum to affordrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-isopropyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylicacid (12) as white solid. Yield: 0.9 g, 93%; MS (ESI) m/z 497.23[M−1]⁻.

Synthesis ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-isopropyl-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(13)

To a solution ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-isopropyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylicacid (12, 0.9 g, 1.807 mmol) in dichloromethane (20 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.0 g, 5.42mmol), 1-hydroxybenzotriazole (0.732 g, 9.03 mmol) andN,N-diisopropylethylamine (1.9 mL, 10.85 mmol) were added at 0° C. andstirred the mixture for 5 min. Dimethylamine hydrochloride (0.734 g,9.03 mmol) was then added at same temperature and the mixture wasstirred for 16 h at 40° C. After completion, reaction mass was dilutedwith dichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to get the crude. The crude waspurified by Combi-flash (12 g, RediSep column) using 15% methanol indichloromethane as eluent. The desired fractions were concentrated toaffordrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-isopropyl-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(13) as white solid. Yield: 0.6 g, 63%; MS (ESI) m/z 526.36[M+1]⁺.

Synthesis ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-2-isopropyl-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 80F)

To a solution ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-isopropyl-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(13, 0.4 g, 0.16 mmol) in N,N-dimethylformamide (10.0 mL), zinc cyanide(0.267 g, 2.28 mmol) and zinc (0.006 g, 0.09 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.009 g, 0.015 mmol) andtris(dibenzylideneacetone)dipalladium (0.021 g, 0.022 mmol) were addedto the reaction and degassing was continued for another 5 min. Thereaction mixture was heated at 150° C. for 4 h. After completion, thereaction mass was diluted with ethyl acetate and washed with cold water.The organic layer was separated and dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure to get thecrude. The crude was purified by Combi-flash (4.0 g, RediSep column)using 3% methanol in dichloromethane as eluent. The compound wasre-purified through reverse HPLC. The desired fractions wereconcentrated to afford rac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-2-isopropyl-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamid(Cpd. No. 80F) as white solid. Yield: 0.100 g, 28%. MS (ESI) m/z473.48[M+1]⁺; UPLC: 99.74%. ¹H NMR (400 MHz, DMSO-d₆) δ 7.52 (d, J=8.5Hz, 2H), 7.42 (s, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.02-6.94 (m, 3H), 6.81(d, J=7.1 Hz, 2H), 5.63 (bs, 1H), 4.81 (d, J=7.3 Hz, 1H), 4.43-4.39 (m,2H), 4.09 (dd, J=7.3 Hz, 13.3 Hz 1H), 3.21 (s, 3H), 2.73 (s, 3H),1.44-1.41 (m, 6H).

Example 814-((3aR,4R,4aR,9bS,9cR)-9b-hydroxy-9-methoxy-2-oxo-4-phenyl-2,3,3a,4,9b,9c-hexahydro-4aH-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-4a-yl)benzonitrile(Cpd. No. 81F)

Synthesis ofrac-(3aR,4R,4aR,9bS,9cR)-4a-(4-bromophenyl)-9b-hydroxy-9-methoxy-4-phenyl-3,3a,4,4a,9b,9c-hexahydro-2H-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-2-one(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 0.500 g, 1.00 mmol) in toluene (10 mL) under nitrogen,molecular sieve (0.125 g), diphenylphosphoryl azide (0.36 g, 1.30 mmol)and triethylamine (0.152 g, 1.50 mmol) were added to the reactionmixture and the reaction was stirred for 15 min at room temperature andthen heated to reflux for 2 h. After completion, the reaction mass wasdiluted with dichloromethane and washed with cold water. The organiclayer was separated and dried over anhydrous sodium sulphate, filteredand concentrated to give crude. The crude was purified by silica gelcolumn chromatography using 0-5% methanol in dichloromethane as eluent.The desired fractions were concentrated to affordrac-(3aR,4R,4aR,9bS,9cR)-4a-(4-bromophenyl)-9b-hydroxy-9-methoxy-4-phenyl-3,3a,4,4a,9b,9c-hexahydro-2H-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-2-one(2) as white solid. Yield: 0.450 g, 90%; MS (ESI) m/z 493.23[M−1]⁻.

Synthesis of4-((3aR,4R,4aR,9bS,9cR)-9b-hydroxy-9-methoxy-2-oxo-4-phenyl-2,3,3a,4,9b,9c-hexahydro-4aH-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-4a-yl)benzonitrile(Cpd. No. 81F)

To a solution ofrac-(3aR,4R,4aR,9bS,9cR)-4a-(4-bromophenyl)-9b-hydroxy-9-methoxy-4-phenyl-3,3a,4,4a,9b,9c-hexahydro-2H-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-2-one(2, 0.45 g, 0.910 mmol) in N,N-dimethylformamide (10 mL), zinc cyanide(0.64 g, 5.46 mmol) and zinc dust (0.007 g, 0.109 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.010 g, 0.0182 mmol) andtris(dibenzylideneacetone)dipalladium (0.025 g, 0.0273 mmol) were addedto the reaction, degassed for additional 5 min and mixture was heated at140° C. for 2 h. After completion, the reaction mass was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by silica gel columnchromatography using 0-4% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-4-((3aR,4R,4aR,9bS,9cR)-9b-hydroxy-9-methoxy-2-oxo-4-phenyl-2,3,3a,4,9b,9c-hexahydro-4aH-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-4a-yl)benzonitrileas white solid. Yield: 0.165 g, 41% (racemic) m/z 442.15 [M+1]⁺. Theenantiomers were separated using chiral preparative HPLC [chiralpak IC(4.6×250 mm, 5)].n-Hexane/Ethanol=40/60 (v/v). Peak 1 (Cpd. No. 81F, 85mg), [α]_(D) −54.7° (c 0.25, CHCl₃), R_(t)=4.510 min, ee: 99.28%, MS(ESI); m/z 442.15 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (s, 1H), 8.22(s, 1H), 8.16 (s, 1H), 7.63 (d, J=8.44 Hz, 2H), 7.31 (d, J=8.44 Hz, 2H),7.14-7.10 (m, 3H), 7.00-6.98 (m, 2H), 6.12 (s, 1H), 5.43 (d, J=8.28 Hz,1H), 4.99 (t, J=9.74 Hz, 1H), 3.97 (s, 3H), 3.50 (d, J=10.88 Hz, 1H).Peak 2 (72 mg), [α]_(D) +69.6° (c 0.398, CHCl₃), R_(t)=8.676 min, ee:99.68%; MS (ESI) m/z 442.15 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 8.31 (s,1H), 8.22 (s, 1H), 8.16 (s, 1H), 7.63 (d, J=8.44 Hz, 2H), 7.31 (d,J=8.44 Hz, 2H), 7.15-7.11 (m, 3H), 7.00-6.98 (m, 2H), 6.12 (s, 1H), 5.43(d, J=8.36 Hz, 1H), 4.99 (t, J=9.74 Hz, 1H), 3.97 (s, 3H), 3.50 (d,J=10.84 Hz, 1H).

Example 82Rac-(4aR,5S,6R,7R,7aS)-3-cyano-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 82F)

Synthesis ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide (2)

To a solution ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(1, 0.30 g, 0.603 mmol) in N,N-dimethylformamide (10 mL), zinc cyanide(0.423 g, 0.362 mmol) and zinc dust (0.0047 g, 0.0724 mmol) were addedat room temperature and the reaction mixture was degassed with argon for15 min. 1,1′-Bis(diphenylphosphino)ferrocene (0.0068 g, 0.0120 mmol) andtris(dibenzylideneacetone)dipalladium (0.0165 g, 0.0181 mmol) were addedto the reaction, degassed for additional 5 min and the mixture washeated at 140° C. for 8 h. After completion, the reaction mass wasdiluted with ethyl acetate and washed with cold water. The organic layerwas separated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by silica gel columnchromatography using 2-3% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to afford rac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(2) as white solid. Yield: 0.180 g, 67%; MS (ESI) m/z 445.42[M+1]⁺.

Synthesis ofrac-(4aR,5S,6R,7R,7aS)-3-bromo-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a, 5,6,7, 7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(3)

To a solution ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide,(2, 0.170 g, 0.382 mmol) in acetonitrile (6 ml), N-bromo succinimide(0.081 g, 0.458 mmol) was added. The reaction mass was stirred for 1 h.After completion, the reaction mass was diluted with ethyl acetate andwashed with cold water. The organic layer was separated and dried overanhydrous sodium sulphate, filtered and concentrated to give crude. Thecrude was purified by silica gel column chromatography using 2-4%methanol in dichloromethane as eluent. The desired fractions wereconcentrated to affordrac-(4aR,5S,6R,7R,7aS)-3-bromo-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(3) as white solid. Yield: 0.10 g, 50%; MS (ESI) m/z 523.14 [M+1]⁺.

Synthesis ofrac-(4aR,5S,6R,7R,7aS)-3-cyano-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 82F)

To a solution ofrac-(4aR,5S,6R,7R,7aS)-3-bromo-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(3, 0.10 g, 0.191 mmol) in N,N-dimethylformamide (4 mL), zinc cyanide(0.134 g, 1.14 mmol) and zinc dust (0.00149 g, 0.0229 mmol) were addedat room temperature and the reaction mixture was degassed with argon for15 min. 1,1′-Bis(diphenylphosphino)ferrocene (0.0021 g, 0.00383 mmol)and tris(dibenzylideneacetone)dipalladium (0.005 g, 0.00574 mmol) wereadded to the reaction, degassed for additional 5 min and mixture washeated at 140° C. for 7 h. After completion, the reaction mass wasdiluted with ethyl acetate and washed with cold water. The organic layerwas separated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by preparative HPLCaffordrac-(4aR,5S,6R,7R,7aS)-3-cyano-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 82F) as white solid. Yield: 0.007 g, 7%; MS (ESI) m/z 470.24[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.55 (d, J=7.64 Hz, 2H), 7.34 (d,J=8.40 Hz, 2H), 7.08-6.96 (m, 3H), 6.83 (d, J=7.12 Hz, 2H), 6.03 (s,1H), 5.69 (bs, 1H), 4.81 (d, J=7.04 Hz, 1H), 4.45 (d, J=13.28 Hz, 1H),4.20-4.11 (m, 1H), 3.98 (s, 3H), 3.21 (s, 3H), 2.74 (s, 3H).

Example 834-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylsulfonyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 83F)

Synthesis of (E)-2-phenylethene-1-sulfonyl chloride (3)

Sulfuryl dichloride (2, 77.70 mL, 960.1 mmol) was added drop wise toanhydrous dimethylformamide (80 mL) at 0° C. under nitrogen and thereaction mixture was stirred at room temperature for 30 min. Styrene (1,50.0 g, 478.4 mmol) was added and the reaction mixture was heated at 90°C. for 2 h. After completion, the mixture was quenched with ice coldwater (1000 ml), the precipitated solid was filtered and dried undervacuum to afford (E)-2-phenylethene-1-sulfonyl chloride (3) as lightbrown solid. Yield: 60.0 g crude.

Synthesis of (E)-1-(styrylsulfonyl)pyrrolidine (5)

To a solution of pyrrolidine (4, 23.2 g, 326.6 mmol) in dichloromethane(60 ml) at 0° C., triethylamine (113.6 mL, 816.8 mmol) and a solution of(E)-2-phenylethene-1-sulfonyl chloride (3 55.0 g, 272.2 mmol) indichloromethane were added drop wise over a period of 15 min. Thereaction mass was slowly brought to room temperature and stirred foradditional 16 h. After completion, the reaction mass was diluted withdichloromethane (500 mL) and water (250 mL). The organic layer wasseparated, washed with water, dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 20% ethyl acetate inhexanes as eluent. The desired fractions were concentrated to afford(E)-1-(styrylsulfonyl)pyrrolidine (5) as Brown solid. Yield: 37.0 g,64.0%; MS (ESI) m/z 238.19 [M+1]⁺.

Synthesis ofrac-(3S,4S,5R)-2-(4-bromophenyl)-8-chloro-5-hydroxy-3-phenyl-4-(pyrrolidin-1-ylsulfonyl)-2,3,4,5-tetrahydro-2,5-methanobenzo[b]oxepin-10-one(7)

A solution of2-(4-bromophenyl)-7-chloro-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one (6,4.0 g, 11.4 mmol) and (E)-1-(styrylsulfonyl)pyrrolidine (5, 27.0 g,113.4 mmol) in dichloromethane (150 mL), acetonitrile (150 mL) andmethanol (150 mL) was placed in a UV reactor flask. The reaction mixturewas irradiated under 400 watts UV light for 72 h. After completion,solvent was removed under reduced pressure and the residue was purifiedover a plug of silica gel eluting the compound with ethyl acetate. Thedesired fractions were concentrated under reduced pressure to affordrac-(3S,4S,5R)-2-(4-bromophenyl)-8-chloro-5-hydroxy-3-phenyl-4-(pyrrolidin-1-ylsulfonyl)-2,3,4,5-tetrahydro-2,5-methanobenzo[b]oxepin-10-one(7) as yellow brown solid. Yield: 4.2 g, crude; MS (ESI) m/z587.08[M−1]⁺.

Synthesis ofrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-7-(pyrrolidin-1-ylsulfonyl)-5a,6,7, 8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one (8)

The crude compoundrac-(3S,4S,5R)-2-(4-bromophenyl)-8-chloro-5-hydroxy-3-phenyl-4-(pyrrolidin-1-ylsulfonyl)-2,3,4,5-tetrahydro-2,5-methanobenzo[b]oxepin-10-one(7, 4.0 g, 6.8 mmol) was suspended in methanol (100 mL) and treated with25% sodium methoxide in methanol (20 mL). The reaction was heated at 80°C. for 3 h. After completion, the solvent was removed under reducedpressure. The crude mixture was diluted with ammonium chloride solutionand extracted with ethyl acetate. The organic phase was separated, driedover anhydrous sodium sulphate and concentrated under reduced pressureto affordrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-7-(pyrrolidin-1-ylsulfonyl)-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(8) as brown solid. Yield: 4.0 g, crude.

Synthesis ofrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyrrolidin-1-ylsulfonyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(9)

To a solution of sodium triacetoxyborohydride (8.65 g, 40.8 mmol),rac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-7-(pyrrolidin-1-ylsulfonyl)-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(8, 4.0 g, 6.80 mmol) in acetonitrile (80 mL), acetic acid (4.08 mL,68.0 mmol) was added. The resulting mixture was stirred for 16 h at roomtemperature. After completion, the reaction mixture was partitionedbetween saturated aqueous sodium bicarbonate solution and ethyl acetate.The organic layer was separated, dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to get the crude. Thecrude was purified by silica gel column chromatography using 1-5%methanol in dichloromethane as eluents. The desired fractions wereconcentrated under reduced pressure to affordrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyrrolidin-1-ylsulfonyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(9) as off white solid. Yield: 0.4 g, 10.0%; MS (ESI) m/z 591.27 [M+1]⁺.

Synthesis of4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylsulfonyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 83F)

To a solution ofrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyrrolidin-1-ylsulfonyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(9, 0.35 g, 0.593 mmol) in N,N-dimethylformamide (7.0 mL), zinc cyanide(0.105 g, 0.889 mmol) and zinc dust (0.004 g, 0.059 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.043 g, 0.059 mmol) andtris(dibenzylideneacetone)dipalladium (0.004 g, 0.0177 mmol) were addedto the reaction, degassed for additional 5 min and mixture was heated at135° C. for 4 h. After completion, the reaction mass was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by silica gel columnchromatography using 2-3% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1-ylsulfonyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrileas white solid. Yield: 0.1 g, 31% (racemic). The enantiomers wereseparated by chiral HPLC [Chiralpak IC (4.6×250)mm, 5μ]n-Hexane/EtOH=50/50 (v/v). Peak 1 (22 mg), [α]_(D) +118.0° (c 0.44,CHCl₃), R_(t)=9.946 min, ee: 99.8%; MS (ESI) m/z 538.14 [M+1]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 8.20 (d, J=1.92 Hz, 1H), 7.68 (d, J=1.92 Hz, 1H),7.49 (bs, 4H), 7.14 (d, J=7.2 Hz, 2H), 7.04 (m, 3H), 6.44 (s, 1H), 5.93(d, J=6.2 Hz, 1H), 4.93 (dd, J=13.58 Hz, 4.06 Hz, 1H), 4.67 (t, J=5.2Hz, 1H), 4.60 (d, J=13.4 Hz, 1H), 3.11 (bs, 2H), 2.66 (bs, 2H), 1.60 (m,4H). Peak 2 (Cpd. No. 83F, 19 mg), [α]_(D) −120.9° (c 0.4, CHCl₃),R_(t)=13.664 min, ee: 99.9%; MS (ESI) m/z 538.14 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.20 (d, J=1.92 Hz, 1H), 7.68 (d, J=1.92 Hz, 1H), 7.49(m, 4H), 7.14 (d, J=7.2 Hz, 2H), 7.04 (m, 3H), 6.44 (s, 1H), 5.93 (d,J=6.2 Hz, 1H), 4.93 (dd, J=13.58 Hz, 4.06 Hz, 1H), 4.67 (t, J=5.2 Hz,1H), 4.60 (d, J=13.4 Hz, 1H), 3.11 (bs, 2H), 2.66 (bs, 2H), 1.60 (m,4H).

Example 84Rac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7-(methylsulfonyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 84F)

Synthesis ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-7-(methylsulfonyl)-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(3)

To a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (3.0 mL, 19.7 mmol)in dimethyl sulfoxide (10 mL), copper(II) bromide (51 mg, 0.23 mmol) wasadded at room temperature in presence of air.Rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(1, 1.5 g, 3.2 mmol) and sodium methanesulfinate (2, 3.36 g, 32.0 mmol)in dimethyl sulfoxide (10.0 mL) were added drop wise to above reactionmixture at room temperature in presence of air. The reaction mixture wasstirred at room temperature for 1 h. After completion (monitored by MS),the reaction mass was diluted with ethyl acetate and washed with coldwater. The organic layer was separated and dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure to affordrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-7-(methylsulfonyl)-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(3) as brown semi solid. Yield: 0.5 g, crude; MS (ESI) m/z 532 [M−1]⁻.

Synthesis ofrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7-(methylsulfonyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 84F)

To a solution of sodium triacetoxyborohydride (1.19 g, 5.62 mmol) andrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-7-(methylsulfonyl)-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(3, 0.5 g, 0.938 mmol) in acetonitrile (25 mL), acetic acid (0.562 mL,9.38 mmol) was added. The resulting mixture was stirred for 6 h at roomtemperature. After completion, reaction mixture was partitioned betweensaturated aqueous sodium bicarbonate solution and ethyl acetate. Theorganic layer was separated, dried over anhydrous sodium sulphate andconcentrated under reduced pressure to get the crude. The crude waspurified by Combi-flash (12 g, RediSep column) using 60% ethyl acetatein hexanes as eluent. The desired fractions were concentrated underreduced pressure to affordrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7-(methylsulfonyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd.No. 84F) as white solid. Yield: 70 mg, 14%. MS (ESI) m/z 536.08 [M+1]⁺;UPLC 99.8%; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.21 (d, J=2.0 Hz, 1H), 7.67(d, J=2.0 Hz, 1H), 7.24 (d, J=8.7 Hz, 2H), 7.19-7.16 (m, 4H) 7.08-7.01(m, 3H), 6.33 (bs, 1H), 6.20 (bs, 1H), 4.83 (dd, J=4.0, 13.5 Hz, 1H),4.77 (d, J=4.4 Hz, 1H), 4.56 (d, J=13.6 Hz, 1H), 2.84 (s, 3H).

Example 85Rac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-7-(methylsulfonyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 85F)

Synthesis ofrac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-7-(methylsulfonyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 85F)

To a solution ofrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7-(methylsulfonyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(1, 0.13 g, 0.242 mmol) in N,N-dimethylformamide (5.0 mL), zinc cyanide(0.033 g, 0.291 mmol) and zinc (0.0016 g, 0.024 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.013 g, 0.024 mmol) andtris(dibenzylideneacetone)dipalladium (0.006 g, 0.007 mmol) were addedto the reaction mixture and degassing was continued for another 5 min.The reaction mixture was heated at 150° C. for 2 h. After completion,the reaction was cooled to room temperature and passed through celitebed. The filtrate was diluted with ethyl acetate and washed with water.The organic layer was separated, dried over anhydrous sodium sulphateand concentrated under reduced pressure to get the crude. The crudecontaining monocyano and dicyano compounds were purified by reversedphase prep-HPLC to affordrac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-7-(methylsulfonyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrileas off white solid. Yield: 84 mg, 45%. The enantiomers were separated bychiral preparative HPLC [chiralpak ID (4.6×250) mm] using 0.1% DEA inn-Hexane/EtOH=70/30 (v/v) mobile phase. Peak 1 (30 mg); [α]_(D) +48.5°(c 0.25, CHCl₃); R_(t)=11.3 min, ee>99%; MS (ESI) m/z 483.08 [M+1]⁺;UPLC: 99.70%; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.22 (d, J=1.92 Hz, 1H), 7.71(d, J=1.8 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H), 7.18(d, J=6.48 Hz, 2H), 7.07-7.00 (m, 3H), 6.45 (s, 1H), 6.26 (d, J=6.2 Hz,1H), 4.94 (dd, J=4.0, 13.8 Hz, 1H), 4.78 (t, J=6.2 Hz, 1H), 4.61 (d,J=13.7 Hz, 1H), 2.86 (s, 3H). Peak-2 (Cpd. No. 85F, 33.0 mg); [α]_(D)−46.6° (c 0.30, CHCl₃); R_(t)=17.2 min, ee>99%; MS (ESI) m/z 483.08[M+1]⁺; UPLC: 99.35%; 1H NMR (400 MHz, DMSO-d₆) δ: 8.22 (d, J=1.8 Hz,1H), 7.71 (d, J=1.8 Hz, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.5 Hz,2H), 7.18 (d, J=6.6 Hz 2H), 7.07-7.00 (m, 3H), 6.45 (s, 1H), 6.26 (d,J=6.3 Hz, 1H), 4.94 (dd, J=4.0 Hz, 13.6 Hz, 1H), 4.78 (t, J=4.52 Hz,1H), 4.62 (d, J=13.8 Hz, 1H), 2.86 (s, 3H).

Example 86(5aR,6S,7R,8S,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-7-(methylsulfonyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-3-carbonitrile(Cpd. No. 86F)

Synthesis of(5aR,6S,7R,8S,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-7-(methylsulfonyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-3-carbonitrile(Cpd. No. 86F)

To a solution ofrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7-(methylsulfonyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(1, 0.13 g, 0.242 mmol) in N,N-dimethylformamide (5.0 mL), zinc cyanide(0.033 g, 0.291 mmol) and zinc (0.0016 g, 0.024 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.013 g, 0.024 mmol) andtris(dibenzylideneacetone)dipalladium (0.006 g, 0.007 mmol) were addedto the reaction mixture and degassing was continued for another 5 min.The reaction mixture was heated at 150° C. for 2 h. After completion,the reaction was cooled to room temperature and passed through celitebed. The filtrate was diluted with ethyl acetate and washed with water.The organic layer was separated, dried over anhydrous sodium sulphateand concentrated under reduced pressure to get the crude. The crudecontaining monocyano and dicyano compounds were purified by reversedphase prep-HPLC to affordrac-(5aR,6S,7R,8S,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-7-(methylsulfonyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-3-carbonitrile(Cpd. No. 86) as off white solid. Yield: 15 mg, 20%; MS (ESI) m/z 474.11[M+1]+; UPLC 99.1%; ¹H NMR (400 MHz, DMSO-d6) δ: 8.66 (d, J=1.4 Hz, 1H),8.04 (d, J=1.4 Hz, 1H), 7.52 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H),7.20 (d, J=6.6 Hz, 2H), 7.07-7.02 (m, 3H), 6.66 (s, 1H), 6.38 (d, J=6.3Hz, 1H), 4.99 (dd, J=3.7 Hz, 13.8 Hz, 1H), 4.83-4.80 (m, 1H), 4.65 (d,J=13.7 Hz, 1H), 2.85 (s, 3H).

Example 87Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(morpholino)methanone(Cpd. No. 87F)

Synthesis ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(morpholino)methanone(Cpd. No. 87F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 0.07 g, 0.1404 mmol) in dichloromethane (2 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.080 g, 0.4214 mmol),hydroxybenzotriazole (0.056 g, 0.4214 mmol) andN,N-diisopropylethylamine (0.126 g, 0.9832 mmol) were added and themixture was stirred for 5 min. Morpholine (2, 0.006 g, 0.7023 mmol) wasthen added at the same temperature and the reaction was stirred for 16 hat room temperature. After completion, the reaction mass was dilutedwith dichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by silica gel columnchromatography using 0-5% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(morpholino)methanone(Cpd. No. 87F) as white solid. Yield: 0.04 g, 51%; MS (ESI) m/z 567.22[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 1H), 7.99 (s, 1H), 7.20 (d,J=8.56 Hz, 2H), 7.09-6.96 (m, 5H), 6.92 (d, J=7.36, 2H), 5.68 (s, 1H),5.20 (d, J=5.48 Hz, 1H), 4.69 (bs, 1H), 4.45 (d, J=13.2 Hz, 1H), 3.88(bs, 4H), 3.76-3.69 (m, 4H), 3.59 (bs, 1H), 3.45-3.42 (m, 2H), 3.11 (bs,1H).

Example 88Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-N-(2,2,2-trifluoroethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 88F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-N-(2,2,2-trifluoroethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 88F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 0.4 g, 0.8 mmol) in dichloromethane (20 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.37 g, 2.4 mmol),hydroxybenzotriazole (0.32 g, 2.4 mmol) and N,N-diisopropylethylamine(0.9 ml, 4.8 mmol) were added at 0° C. and stirred the mixture for 5min. 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride (0.39 g, 3.0mmol) was then added and the reaction mixture was stirred for 3 h atroom temperature. After completion, reaction mass was diluted withdichloromethane and washed with cold water. The organic layer was driedover anhydrous sodium sulphate, filtered and concentrated under reducepressure to get the crude. The crude product was purified by Combi-flash(4.0 g, RediSep column) using 3% methanol in dichloromethane as eluent.The crude obtained was submitted for reverse phase prep HPLC. Thedesired fractions were lyophilized to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-N-(2,2,2-trifluoroethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 88F) as white solid. Yield: 12 mg, 2.5%; MS (ESI) m/z 593.23[M+1]⁺UPLC: 99.79%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (s, 1H), 8.00 (s,1H), 7.22 (d, J=12.2 Hz, 2H), 7.14-7.03 (m, 4H), 6.97 (d, J=6.7 Hz, 1H),6.92-6.85 (m, 2H), 5.76 (s, 1H), 5.23 (d, J=5.4 Hz, 1H), 4.81 (t, J=5.2Hz, 1H), 4.44 (d, J=13.4 Hz, 1H), 4.31-4.23 (m, 2H), 3.97-3.88 (m, 1H),3.88 (s, 3H), 3.42 (s, 3H).

Example 89Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-cyclopropyl-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 89F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-cyclopropyl-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 89F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.50 g, 3.01 mmol) in dichloromethane (40 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (1.73 g, 9.05 mmol),hydroxybenzotriazole (1.38 g, 9.05 mmol) and N,N-diisopropylethylamine(2.72 g, 21.12 mmol) were added and the mixture was stirred for 5 min.Cyclopropylamine (2, 0.861 g, 15.09 mmol) was then added at the sametemperature and the reaction was stirred for 16 h at room temperature.After completion, the reaction mass was diluted with dichloromethane andwashed with cold water. The organic layer was separated and dried overanhydrous sodium sulphate, filtered and concentrated to give crudeproduct. The crude product was purified by silica gel columnchromatography using 0-5% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-cyclopropyl-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 89F) as white solid. Yield: 1.3 g, 86% MS (ESI) m/z 537.2[M+1]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.28 (d, J=4.08 Hz, 1H), 8.08 (s,1H), 7.98 (s, 1H), 7.22 (d, J=8.56 Hz, 2H), 7.08-6.95 (m, 7H), 5.65 (s,1H), 5.08 (d, J=4.16 Hz, 1H), 4.54 (t, J=4.18 Hz, 1H), 4.34 (d, J=14.0Hz, 1H), 3.87 (s, 3H), 3.78 (dd, J=14.16 Hz, 6.16 Hz, 1H), 2.55 (d,J=3.8 Hz, 1H), 0.55 (d, J=6.64 Hz, 2H), 0.43-0.40 (m, 1H), 0.28-0.26 (m,1H).

Example 90Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-N-(2,2,2-trifluoroethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 90F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-N-(2,2,2-trifluoroethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 90F)

To a solution of(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 0.5 g, 1.0 mmol) in dichloromethane (20 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.47 g, 3.0 mmol),hydroxybenzotriazole (0.40 g, 3.0 mmol) and N,N-diisopropylethylamine(0.9 ml, 5.0 mmol) were added at 0° C. and stirred the mixture for 5min. 2,2,2-Trifluoroethan-1-amine (2, 0.30 g, 3.0 mmol) was added toabove solution and the reaction mixture was stirred for 3 h at roomtemperature. After completion, reaction mass was diluted withdichloromethane and washed with cold water. The organic layer was driedover anhydrous sodium sulphate, filtered and concentrated under reducedpressure to get the crude. The crude was purified by Combi-flash (4 gRediSep column) using 3% methanol in dichloromethane as eluent. Thecrude compound was submitted for reverse phase prep HPLC. The desiredfractions were lyophilized to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-N-(2,2,2-trifluoroethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 90F) as white solid. Yield: 217 mg, 40%; MS (ESI) m/z 579.21[M+1]⁺, UPLC: 99.29%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (t, J=6.1 Hz,1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.23 (d, J=8.6 Hz, 2H), 7.06-7.02 (m,4H), 6.98 (d, J=7.0 Hz, 1H), 6.94 (d, J=7.4 Hz, 2H), 5.67 (s, 1H), 5.08(d, J=4.9 Hz, 1H), 4.63 (d, J=4.8 Hz, 1H), 4.37 (d, J=12.7 Hz, 1H), 3.96(dd, J=4.8 Hz, 14.2 Hz, 1H), 3.90 (s, 3H), 3.80 (m, 1H).

Example 91Rac-(5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7,7-difluoro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 91F)

Synthesis ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-8-(butylamino)-3-chloro-6-phenyl-5a,6-dihydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol (2)

To a solution ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(1, 0.50 g, 1.09 mmol) in benzene (5.0 ml), trifluoroacetic acid (0.01ml, cat) was added followed by addition of n-butyl amine (0.12 g, 1.64mmol). The reaction mixture was stirred at 100° C. After completion, Themixture was diluted with ethyl acetate (100 mL) and water (50 mL). Theorganic layer was separated and washed with water, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toaffordrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-8-(butylamino)-3-chloro-6-phenyl-5a,6-dihydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(2) as yellow solid. Yield: 0.6 g, 64%; MS (ESI) m/z 511.29 [M+1]⁺.

Synthesis of rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-7,7-difluoro-6-phenyl-6,7-dihydro-8H-cyclopenta[4,5]furo[3,2-b]pyridine-8, 8, 8a(5aH)-triol (3)

To a solution ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-8-(butylamino)-3-chloro-6-phenyl-5a,6-dihydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(2, 0.6 g, 1.1 mmol) in acetonitrile (10 ml) at 0° C., selectfluor (0.83g, 2.3 mmol) was added in one portion followed by sodium sulfate (0.6g). The reaction mass was stirred for 12 h at 70° C. After completion,the mixture was diluted with ethyl acetate (100 mL) and water (50 mL).The organic layer was separated, washed with water, dried over anhydroussodium sulfate, and concentrated under reduced pressure to affordrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-7,7-difluoro-6-phenyl-6,7-dihydro-8H-cyclopenta[4,5]furo[3,2-b]pyridine-8,8,8a(5aH)-triol(3) as yellow solid. Yield: 0.37 g crude MS (ESI) m/z 509.95 [M+1]⁺.

Synthesis of rac-(5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7,7-difluoro-6-phenyl-5a, 6, 7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd. No.91F)

To a solution ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-7,7-difluoro-6-phenyl-6,7-dihydro-8H-cyclopenta[4,5]furo[3,2-b]pyridine-8,8,8a(5aH)-triol(3, 0.2 g, 0.407 mmol) in acetonitrile (5 mL) and acetic acid (0.5 ml,8.14 mmol) was added sodium triacetoxyborohydride (0.51 g, 2.4 mmol).The resulting mixture was stirred for 24 h at room temperature. Aftercompletion, the reaction mixture was partitioned between saturatedaqueous sodium bicarbonate solution and ethyl acetate. The organic layerwas separated, dried over anhydrous sodium sulphate, and concentratedunder reduced pressure to get the crude. The crude product was purifiedby preparative HPLC to affordrac-(5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7,7-difluoro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 91F) as white solid. Yield: 3 mg, 1.5%; MS (ESI) m/z 494.34[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (d, J=2 Hz, 1H), 7.73 (d, J=2Hz, 1H), 7.33 (d, J=8.8 Hz, 2H), 7.19 (m, 7H), 6.57 (d, J=5.6 Hz, 1H),6.42 (s, 1H), 4.57 (m, 1H), 4.42 (m, 1H).

Example 92Rac-(5aR,6R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6-dihydrospiro[cyclopenta[4,5]furo[3,2-b]pyridine-7,1′-cyclopropane]-8,8a(8H)-diol(Cpd. No. 92F)

Synthesis ofrac-(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-7-methylene-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(3)

A solution ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(1, 0.150 g, 0.32 mmol) in tetrahydrofuran (3 mL) was cooled to 0° C.and lithium diisopropylamide (2.0 M in THF) (0.48 mL, 0.96 mmol) wasadded. The reaction mixture was stirred at the same temperature for 30min. N-methyl-N-methylenemethanaminium iodide (2, 0.207 g, 1.12 mmol)was then added and reaction mixture was stirred at room temperature for3 h. Reaction mixture was quenched with saturated ammonium chloridesolution and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulphate, filtered and concentrated to give crudeproduct. Crude product obtained was purified by column chromatographyusing silica gel (100-200 mesh) and 0-10% ethyl acetate in hexane toaffordrac-(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-7-methylene-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(3) as off white solid. Yield: 0.075 g, 49%; MS (ESI) m/z 467.90 [M+1]⁺.

Synthesis ofrac-(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,8a-dihydrospiro[cyclopenta[4,5]furo[3,2-b]pyridine-7,1′-cyclopropan]-8(6H)-one(5)

To a solution ofrac-(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-7-methylene-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(3, 0.200 g, 0.42 mmol) in DMSO (2 mL) was added sodium hydride (0.016g, 0.42 mmol) and reaction mixture was stirred at room temperature for15 minutes. A solution of trimethylsulfoxonium iodide (4, 0.092 g, 0.42mmol) in DMSO:THF (1:1) (2 mL) was then added at 0° C. and the reactionmixture was stirred at 0° C. for 1 hour. The reaction mixture wasquenched with water and extracted with ethyl acetate. The organic phasewas dried over anhydrous sodium sulphate, filtered and concentrated toaffordrac-(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,8a-dihydrospiro[cyclopenta[4,5]furo[3,2-b]pyridine-7,1′-cyclopropan]-8(6H)one(5) as light brown sticky solid which was directly used for nextreaction without purification. Yield: 0.180 g, crude; MS (ESI) m/z481.93 [M+1]⁺.

Synthesis ofrac-(5aR,6R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6-dihydrospiro[cyclopenta[4,5]furo[3,2-b]pyridine-7,1′-cyclopropane]-8,8a(8H)-diol(Cpd. No. 92F)

To a solution ofrac-(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,8a-dihydrospiro[cyclopenta[4,5]furo[3,2-b]pyridine-7,1′-cyclopropan]-8(6H)-one (5, 0.180 g, 0.37 mmol) in acetonitrile (5mL), at 0° C. were added acetic acid (0.22 mL, 3.7 mmol) and sodiumtriacetoxyborohydride (0.470 g, 2.22 mmol) and the reaction mixture wasstirred at room temperature for 16 h. The reaction mixture was quenchedwith saturated sodium bicarbonate solution and extracted with ethylacetate. The organic layer was washed with water, dried over anhydroussodium sulphate, filtered and concentrated to give crude product. Thecrude product obtained was purified by preparative HPLC to affordrac-(5aR,6R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6-dihydrospiro[cyclopenta[4,5]furo[3,2-b]pyridine-7,1′-cyclopropane]-8,8a(8H)-diol(Cpd. No. 92F) as white solid. Yield: 0.035 g, 19.4%; MS (ESI) m/z484.43 [M+1]⁺¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (d, J=2.0 Hz, 1H), 7.56(d, J=2.0 Hz, 1H), 7.24 (d, J=7.0 Hz, 2H), 7.14-7.07 (m, 3H), 7.01 (d,J=8.6 Hz, 2H), 6.92 (d, J=6.4 Hz, 2H), 6.03 (s, 1H), 5.17 (d, J=5.6 Hz,1H), 4.84 (d, J=5.6 Hz, 1H), 3.43 (s, 1H), 0.56-0.49 (m, 2H), 0.36-0.29(m, 1H), 0.13-0.06 (m, 1H).

Example 93Rac-(5aR,6S,7R,8S,8aS)-7-(benzylsulfonyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 93F)

Synthesis ofrac-(5aR,6S,8aR)-7-bromo-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(2)

Bromine (0.24 mL, 4.7 mmol) was added to a solution ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(1, 2.0 g, 4.3 mmol) in acetonitrile (30 mL) at 0° C. The reactionmixture was then allowed to come to room temperature and stirred for 40h. The reaction mixture was diluted with water and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulphate,filtered and concentrated to give crude product which was purified bycolumn chromatography using silica gel (100-200 mesh) and 0-30% ethylacetate in hexane to affordrac-(5aR,6S,8aR)-7-bromo-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(2) as yellow solid. Yield: 1.7 g, 73.9%; MS (ESI) m/z 532.13[M−1]⁻.

Synthesis ofrac-(5aR,6S,8aR)-7-(benzylthio)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(4)

The solution ofrac-(5aR,6S,8aR)-7-bromo-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(2, 0.200 g, 0.37 mmol) in benzyl mercaptan (3, 1 mL) was heated at 70°C. for 2 h. Reaction mixture was cooled to giverac-(5aR,6S,8aR)-7-(benzylthio)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(4) as yellow viscous liquid which was directly used for next reactionwithout purification. Yield: 0.200 g, crude; MS (ESI) m/z 578.03 [M+1]⁺.

Synthesis ofrac-(5aR,6S,8aS)-7-(benzylthio)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (5)

To the solution ofrac-(5aR,6S,8aR)-7-(benzylthio)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(4, 0.350 g, 0.6 mmol) in acetonitrile (10 mL) at 0° C. were addedacetic acid (0.72 mL, 12.0 mmol) and sodium triacetoxy borohydride (1.5g, 7.2 mmol). The reaction mixture was then stirred at room temperaturefor 16 h. The reaction mixture was then quenched with saturated sodiumbicarbonate solution and extracted with ethyl acetate. The organic layerwas washed with water, dried over anhydrous sodium sulphate, filteredand concentrated to give crude product which was purified by columnchromatography using silica gel (100-200 mesh) and 0-30% ethyl acetatein hexane to affordrac-(5aR,6S,8aS)-7-(benzylthio)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(5) as white solid. Yield: 0.150 g, crude; MS (ESI) m/z 580.03 [M+1]+.

Synthesis ofrac-(5aR,6S,7R,8S,8aS)-7-(benzylsulfonyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 93F)

To a solution ofrac-(5aR,6S,8aS)-7-(benzylthio)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(5, 0.210 g, 0.36 mmol) in methanol (5 mL) at 0° C. was added a solutionof oxone (0.274 g, 1.8 mmol) in water (5 mL) and reaction mixture wasstirred at room temperature for 24 h. Reaction mixture was concentrated,diluted with water, and extracted with dichloromethane. The organiclayer was washed with water, dried over anhydrous sodium sulphate,filtered and concentrated to give crude product, which was purified bycolumn chromatography using silica gel (100-200 mesh) and 0-50% ethylacetate in hexane to give mixture, which was purified by preparativeHPLC to affordrac-(5aR,6S,7R,8S,8aS)-7-(benzylsulfonyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 93F) as white solid. Yield: 0.026 g, 11.8%; MS (ESI) m/z612.12 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (s, 1H), 7.70 (s, 1H),7.32-7.31 (m, 3H), 7.28-7.25 (m, 2H), 7.20 (d, J=8.7 Hz, 2H), 7.17-7.12(m, 4H), 7.10-7.05 (m, 3H), 6.4 (bs, 2H), 4.94-4.87 (m, 2H), 4.64 (d,J=13.2 Hz, 1H), 4.38 (d, J=13.0 Hz, 1H) and 4.30 (d, J=12.9 Hz, 1H).

Example 94Rac-4-((5aR,6S,7R,8S,8aS)-7-(benzylsulfonyl)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 94F)

Synthesis ofrac-4-((5aR,6S,7R,8S,8aS)-7-(benzylsulfonyl)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 94F)

To a solution ofrac-(5aR,6S,7R,8S,8aS)-7-(benzylsulfonyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(1, 0.018 g, 0.029 mmol) in N,N-dimethylformamide (1 mL), zinc cyanide(0.020 g, 0.176 mmol) and zinc dust (0.0002 g, 0.0034 mmol) were addedat room temperature and the reaction mixture was degassed with argon for15 min. 1,1′-Bis(diphenylphosphino)ferrocene (0.0003 g, 0.000058 mmol)and tris(dibenzylideneacetone)dipalladium (0.0008 g, 0.00008 mmol) wereadded to the reaction, degassed for additional 5 min and reactionmixture was heated at 130° C. for 3 h. After completion, the reactionmass was diluted with ethyl acetate and washed with cold water. Theorganic layer was separated and dried over anhydrous sodium sulphate,filtered and concentrated to give crude product. The crude product waspurified by preparative HPLC to affordrac-4-((5aR,6S,7R,8S,8aS)-7-(benzylsulfonyl)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 94F) as white solid. Yield: 0.008 g, 50%; MS (ESI) m/z 559.2[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (s, 1H), 7.74 (s, 1H), 7.55 (d,J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.33-7.31 (m, 3H), 7.19 (d, J=6.4Hz, 2H), 7.15-7.13 (m, 2H), 7.08-7.03 (m, 3H), 6.49 (s, 1H), 6.39 (d,J=6.2 Hz, 1H), 5.04 (dd, J=4.4 Hz, 1H), 4.91 (t, J=6 Hz, 1H), 4.70 (d,J=13.6 Hz, 1H), 4.40 (d, J=8.2 Hz, 1H), 4.32 (d, J=8.2 Hz, 1H).

Example 95(4bS,5R,6R,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 95F)

Synthesis of(E)-3-(4-bromophenyl)-1-(3-hydroxypyridin-4-yl)prop-2-en-1-one (3)

To a solution of 1-(3-hydroxypyridin-4-yl)ethan-1-one (1, 3.0 g, 21.89mmol) and 4-bromobenzaldehyde (2, 4.05 g, 21.89 mmol) in methanol (15mL), sodium hydroxide (2.62 g, 65.67 mmol) was added and the mixture washeated to reflux for 30 min. After completion, the reaction mass wascooled to room temperature, the precipitated solid was filtered, washedwith water, n-pentane and dried under vacuum to afford(E)-3-(4-bromophenyl)-1-(3-hydroxypyridin-4-yl)prop-2-en-1-one (3) asyellow solid. Yield: 6.0 g, 90.0%; MS (ESI) m/z 304.18 [M+1]⁺.

Synthesis of 2-(4-bromophenyl)-3-hydroxy-4H-pyrano[2,3-c]pyridin-4-one(4)

To a solution of(E)-3-(4-bromophenyl)-1-(3-hydroxypyridin-4-yl)prop-2-en-1-one (3, 6.0g, 19.72 mmol) in ethanol (120 mL) at 0° C., sodium hydroxide (5.52 g,138.0 mmol) was added followed by the addition of 30% aqueous hydrogenperoxide (15.65 mL, 138.0 mmol). The reaction mass was stirred for 30min at 60° C. After completion, the reaction mass was cooled andneutralized by the addition of 6 M hydrogen chloride to pH ˜7. The solidobtained was filtered, washed with cold ethanol, pentane and dried undervacuum to afford2-(4-bromophenyl)-3-hydroxy-4H-pyrano[2,3-c]pyridin-4-one (4) as Paleyellow solid. Yield: 3.2 g, 51%; MS (ESI) m/z 316.16[M−1]⁻.

Synthesis of rac-methyl(2S,3S,4S,5R)-2-(4-bromophenyl)-5-hydroxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(6)

A solution of 2-(4-bromophenyl)-3-hydroxy-4H-pyrano[2,3-c]pyridin-4-one(4, 3.5 g, 11.0 mmol) and methyl cinnamate (5, 17.84 g, 110.0 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedunder 400 watts UV light for 24 h. After completion, solvent was removedunder reduced pressure and the residue was purified over a plug ofsilica gel eluting the compound with 5% methanol in dichloromethane. Thedesired fractions were concentrated under reduced pressure to affordrac-methyl(2S,3S,4S,5R)-2-(4-bromophenyl)-5-hydroxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(6) as Yellow solid. Yield: 4.0 g, 77%; MS (ESI) m/z 510.05[M+31]⁺.

Synthesis of rac-methyl(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7)

A solution of rac-methyl(2S,3S,4S,5R)-2-(4-bromophenyl)-5-hydroxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(6, 4.0 g, 8.33 mmol) was suspended in methanol (40 mL) and treated with25% sodium methoxide in methanol (4.5 mL). The reaction was heated at80° C. for 4 h. After completion, the solvent was removed under reducedpressure. The crude was diluted with ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and concentrated under reduced pressure to affordrac-methyl(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7) as white solid. Yield: 3.0 g, 75%; MS (ESI) m/z 480.04 [M+1]⁺.

Synthesis of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8)

A solution of rac-methyl(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7, 3.0 g, 6.24 mmol) in acetonitrile (60 mL) was cooled at 0° C.,acetic acid (3.74 g, 62.40 mmol) and sodium triacetoxyborohydride (13.54g, 6.24 mmol) were added. The resulting mixture was stirred for 12 h atroom temperature. After completion, the reaction mixture was partitionedbetween saturated aqueous sodium bicarbonate solution and ethyl acetate.The organic layer was separated and dried over sodium sulphate, filteredand concentrated to give crude. The crude was purified by silica gelcolumn chromatography eluting with 2-3% in methanol in dichloromethane.The desired fractions were concentrated to afford rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8) as Yellow solid. Yield: 1.5 g, 50.0%; MS (ESI) m/z 482.31 [M+1]⁺.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (9)

To a solution of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8, 1.0 g, 2.07 mmol) in methanol, tetrahydrofuran and water (2:1:1, 12mL), lithium hydroxide (0.497 g, 20.7 mmol) was added and the reactionwas stirred for 6 h at room temperature. After completion, the reactionmass was concentrated and cooled to 0° C. and acidified with 1 Mhydrochloric acid to pH ˜2-3. The precipitated solid was filtered anddried under vacuum to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (9) as white solid. Yield: 0.75 g, 77%; MS (ESI) m/z 468.25 [M+1]+.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(10)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (9, 0.75 g, 1.59 mmol) in dichloromethane (15 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.742 g, 4.78 mmol),hydroxybenzotriazole (0.732 g, 4.78 mmol) and N,N-diisopropylethylamine(1.71 mL, 9.57 mmol) were added and the mixture was stirred for 5 min.Dimethylamine hydrochloride (0.650 g, 7.9 mmol) was then added at thesame temperature and the mixture was stirred for 16 h at roomtemperature. After completion, the reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by silica gel column chromatographyeluting with 2-3% methanol in dichloromethane. The desired fractionswere concentrated to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(10) as off white solid; Yield: 0.50 g, 64%; MS (ESI) m/z 495.11 [M+1]+.

Synthesis of(4bS,5R,6R,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 95F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(10, 0.200 g, 0.40 mmol) in N,N-dimethylformamide (4.0 mL), zinc cyanide(0.285 g, 2.42 mmol) and zinc (0.0031 g, 0.048 mmol) were added at roomtemperature and degassed the mixture with argon for 15 minute.1,1′-Bis(diphenylphosphino)ferrocene (0.006 g, 0.008 mmol) andtris(dibenzylideneacetone)dipalladium (0.008 g, 0.012 mmol) were addedto the reaction and degassing was continued for another 5 min. Thereaction mixture was heated at 140° C. for 3 h. After completion, thereaction mass was diluted with ethyl acetate and washed with cold water.The organic layer was separated and dried over sodium sulphate, filteredand concentrated to give crude. The crude was purified by silica gelcolumn chromatography eluting with 2-3% methanol in dichloromethane. Thedesired fractions were concentrated to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamideas white solid. Yield: 0.11 g, 62%. (Racemic mixture); MS (ESI) m/z442.36 [M+1]+; The enantiomers were separated by chiral preparative HPLC[chiralpak IA (4.6×250) mm, 5μ]. Peak 1 (Cpd. No. 95F, 24 mg), [α]_(D)−125.4° (c 0.23, CHCl₃), R_(t)=4.356 min, ee>99% ¹H NMR (400 MHz,DMSO-d₆) δ 8.48 (s, 1H), 8.24 (d, J=4.76 Hz, 1H), 7.57 (d, J=8.52 Hz,2H), 7.47 (d, J=5.00 Hz, 1H), 7.40 (d, J=8.48 Hz, 2H), 7.05 (m, 3H), 6.8(d, J=7.08 Hz, 2H) 5.91 (s, 1H), 5.74 (d, J=6.08 Hz, 1H), 4.94 (t,J=7.04 Hz, 1H), 4.31 (d, J=13.2 Hz, 1H), 4.18 (dd, J=7.56 Hz, J=7.60 Hz,1H), 3.23 (s, 3H), 2.73 (s, 3H); Peak-2 (24 mg), [α]_(D) +122.3° (c0.264, CHCl₃), R_(t)=14.114 min, ee>99% ¹H NMR (400 MHz, DMSO-d₆) δ 8.48(s, 1H), 8.24 (d, J=4.76 Hz, 1H), 7.57 (d, J=8.52 Hz, 2H), 7.47 (d,J=5.00 Hz, 1H), 7.40 (d, J=8.48 Hz, 2H), 7.05 (m, 3H), 6.8 (d, J=7.08Hz, 2H), 5.91 (s, 1H), 5.74 (d, J=6.00 Hz, 1H), 4.94 (t, J=7.08 Hz, 1H),4.31 (d, J=13.2 Hz, 1H), 4.19 (dd, J=7.60, 7.48 Hz, 1H), 3.23 (s, 3H),2.73 (s, 3H).

Example 96Rac-(4bS,5R,6R,7S,7aR)-4-cyano-7a-(4-cyanophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 96F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-4-cyano-7a-(4-cyanophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 96F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-4-chloro-7a-(4-cyanophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 0.2 g, 0.419 mmol) in N,N-dimethylformamide (4 mL), zinc cyanide(0.98 g, 8.3 mmol) and zinc dust (0.013 g, 0.201 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15minutes and tetrakis(triphenylphosphine)palladium (0) (0.132 g, 0.117mmol) was added to the reaction mixture, degassed for additional 5 minand reaction mixture was heated at 140° C. for 3 h. After completion,the reaction mass was diluted with ethyl acetate and washed with coldwater. The organic layer was separated and dried over anhydrous sodiumsulphate, filtered and concentrated to give crude product. The crudeproduct was purified by preparative HPLC. The desired fractions wereconcentrated and lyophilized to affordrac-(4bS,5R,6R,7S,7aR)-4-cyano-7a-(4-cyanophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 96F) as white solid. Yield: 0.013 g, 6.6%; MS (ESI) m/z 467.27[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.68 (s, 1H), 7.60 (d,J=8.4 Hz, 2H), 7.41 (d, J=8 Hz, 2H), 7.08-7.03 (m, 3H), 6.81 (d, J=6.8Hz, 2H), 4.34 (d, J=7.6 Hz, 1H), 3.96-3.91 (m, 1H), 3.82 (d, J=13.2 Hz,1H), 3.26 (s, 3H), 2.77 (s, 3H).

Example 97Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4-chloro-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 97F)

Synthesis of 3-chloro-5-((4-methoxybenzyl) oxy) isonicotinonitrile (2)

To a solution of 3,5-dichloroisonicotinonitrile (1, 50.00 g, 289.0 mmol)in tetrahydrofuran (500 ml) at 0° C., 60% sodium hydride (13.87 g, 346.8mmol) was added followed by addition of (4-methoxyphenyl)methanol (33.67ml, 289.0 mmol) and the reaction mixture was stirred at room temperaturefor 10 min. After completion, the mixture was quenched with ice coldwater (1000 ml), solid compound obtained was then filtered and dried toafford 3-chloro-5-((4-methoxybenzyl)oxy)isonicotinonitrile (2) as whitesolid. Yield: 85.0 g, 95%; MS (ESI) m/z 275.16 [M+1]⁺.

Synthesis of 1-(3-chloro-5-hydroxypyridin-4-yl) ethan-1-one (3)

To a solution of 3-chloro-5-((4-methoxybenzyl)oxy)isonicotinonitrile (2,10.0 g, 36.4 mmol) in dry tetrahydrofuran (60 ml) at 0° C., methylmagnesium bromide (109.4 mL, 328.4 mmol) was added drop wise over aperiod of 30 min. The reaction mass was slowly brought to roomtemperature and stirred for additional 12 h. After completion, thereaction mass was quenched with 6 M hydrochloric acid to pH ˜3 andstirred for 3 h. The mixture was diluted with ethyl acetate (100 mL),water (50 mL) and basified with sodium bicarbonate up to pH-10. Theorganic layer was separated, washed with water, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using 25%ethyl acetate in hexanes as eluent. The desired fractions wereconcentrated to afford 1-(3-chloro-5-hydroxypyridin-4-yl) ethan-1-one(3) as light yellow solid. Yield: 2.94 g, 47%; MS (ESI) m/z170.17[M−1]⁺.

Synthesis of (E)-3-(4-bromophenyl)-1-(3-chloro-5-hydroxypyridin-4-yl)prop-2-en-1-one (5)

To a solution of 1-(3-chloro-5-hydroxypyridin-4-yl)ethan-1-one (3, 1.3g, 7.57 mmol) in methanol (13 mL), sodium hydroxide (0.9 g, 22.7 mmol)was added followed by addition of 4-bromobenzaldehyde (4, 1.4 g, 7.57mmol). The reaction was heated to reflux for 30 min. After completion,the reaction mass was cooled to room temperature then diluted with water(20 mL).

Solid obtained was filtered and dried. The solid obtained was trituratedwith pentane, filtered and dried under vacuum to afford(E)-3-(4-bromophenyl)-1-(3-chloro-5-hydroxypyridin-4-yl)prop-2-en-1-one(5) as yellow solid. Yield: 2.5 g, 98%; MS (ESI) m/z 336.1[M−1]⁺.

Synthesis of 2-(4-bromophenyl)-5-chloro-3-hydroxy-4H-pyrano[2,3-c]pyridin-4-one (6)

To a solution of(E)-3-(4-bromophenyl)-1-(3-chloro-5-hydroxypyridin-4-yl)prop-2-en-1-one(5, 2.5 g, 7.41 mmol) in ethanol (75 mL) at 0° C., sodium hydroxide(0.36 g, 8.90 mmol) was added followed by the addition of 30% aqueoushydrogen peroxide (5.88 mL, 51.9 mmol). The reaction mixture was heatedat 60° C. for 30 min. After completion, the reaction mixture was cooledand neutralized to pH ˜7 by the addition of 6 M hydrogen chloride. Thesolid obtained was filtered and dried to get crude compound. The crudeproduct obtained was triturated with ethanol, filtered and dried undervacuum to afford2-(4-bromophenyl)-5-chloro-3-hydroxy-4H-pyrano[2,3-c]pyridin-4-one (6)as yellow solid. Yield: 0.7 g, 26.0%; MS (ESI) m/z 351.3 [M+1]⁺.

Synthesis of rac-methyl(3S,4S,5R)-2-(4-bromophenyl)-6-chloro-5-hydroxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(8)

A solution of2-(4-bromophenyl)-5-chloro-3-hydroxy-4H-pyrano[2,3-c]pyridin-4-one (6,4.0 g, 11.3 mmol) and methyl cinnamate (7, 21.0 g, 113.4 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedunder 400 watts UV light for 18 h. After completion, solvent was removedunder reduced pressure and the residue was purified over a plug ofsilica gel eluting the compound with ethyl acetate. The desiredfractions were concentrated under reduced pressure to afford rac-methyl(3S,4S,5R)-2-(4-bromophenyl)-6-chloro-5-hydroxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(8) as yellow brown solid. Yield: 4.9 g, crude. MS (ESI) m/z512.42[M−1]⁺.

Synthesis of rac-methyl(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4-chloro-4b-hydroxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(9)

The crude compound rac-methyl(3S,4S,5R)-2-(4-bromophenyl)-6-chloro-5-hydroxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(8, 4.9 g) was suspended in methanol (100 mL) and treated with 25%sodium methoxide solution in methanol (20 mL). The reaction was heatedat 80° C. for 3 h. After completion, the solvent was removed underreduced pressure. The crude was diluted with ammonium chloride solutionand extracted with ethyl acetate. The organic layer was separated, driedover anhydrous sodium sulphate and concentrated under reduced pressureto afford of rac-methyl(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4-chloro-4b-hydroxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(9) as brown solid. Yield: 4.2 g, crude.

Synthesis of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4-chloro-4b,5-dihydroxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(10)

To a solution of rac-methyl(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4-chloro-4b-hydroxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(9, 4.0 g, 7.79 mmol) in acetonitrile (40 mL) and acetic acid (4.6 ml,77.9 mmol), sodium triacetoxyborohydride (16.91 g, 77.9 mmol) was added.The resulting mixture was stirred at room temperature for 4 h. Aftercompletion, the reaction mixture was partitioned between saturatedaqueous sodium bicarbonate solution and ethyl acetate. The organic layerwas separated, dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to get the crude product. The crudeproduct was purified by silica gel column chromatography using 0-5%methanol in dichloromethane as eluent. The desired fractions wereconcentrated under reduced pressure to afford rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4-chloro-4b,5-dihydroxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(10) as off white solid. Yield: 1.7 g, 42.5%; MS (ESI) m/z 516.16[M+1]+.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4-chloro-4b,5-dihydroxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (11)

To a solution of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4-chloro-4b,5-dihydroxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(10, 1.75 g, 3.39 mmol) in methanol:THF: water (2:1:1, 50 mL), lithiumhydroxide (1.63 g, 67.9 mmol) was added and the reaction was stirred for2 h at room temperature. After completion, the reaction mixture wascooled to 0° C. and acidified with 1 M hydrochloric acid to pH ˜2-3. Theprecipitate obtained was filtered and dried under vacuum to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4-chloro-4b,5-dihydroxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (11) as white solid. Yield: 1.6 g, 94%; MS (ESI) m/z 502.1 [M+1]⁺.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4-chloro-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 97F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4-chloro-4b,5-dihydroxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (11, 1.6 g, 3.19 mmol) in dichloromethane (20 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (1.8 g, 9.57 mmol),hydroxybenzotriazole (1.46 g, 9.57 mmol) and N,N-diisopropylethylamine(3.5 g, 19.1 mmol) were added and the mixture was stirred for 5 min.Dimethylamine hydrochloride (1.3 g, 15.9 mmol) was then added at thesame temperature and the reaction was stirred for 16 h at roomtemperature. After completion, the reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel column chromatography using 0-5% methanol in dichloromethaneas eluent. The desired fractions were concentrated to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4-chloro-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 97F) as white solid. Yield: 0.8 g, 48%; MS (ESI) m/z 529.16[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 1H), 8.16 (s, 1H), 7.22 (d,J=8.8 Hz, 2H), 7.09-7.02 (m, 4H), 6.96-6.93 (m, 3H), 6.05 (s, 1H), 5.45(s, 1H), 4.76 (d, J=3.6 Hz, 1H), 4.56 (d, J=13.2 Hz, 1H), 4.28 (m, 1H),3.30 (s, 3H), 2.79 (s, 3H).

Example 98(4bS,5R,6R,7S,7aR)-4-chloro-7a-(4-cyanophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 98F)

Synthesis of(4bS,5R,6R,7S,7aR)-4-chloro-7a-(4-cyanophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 98F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4-chloro-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 0.6 g, 1.13 mmol) in N,N-dimethylformamide (10 mL), zinc cyanide(0.129 g, 0.568 mmol) and zinc dust (0.0088 g, 0.13 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.012 g, 0.022 mmol) andtris(dibenzylideneacetone)dipalladium (0.065 g, 0.056 mmol) were addedto the reaction, degassed for additional 5 min and reaction mixture washeated at 140° C. for 3 h. After completion, the reaction mixture wasdiluted with ethyl acetate and washed with cold water. The organic layerwas separated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel column chromatography using 2-3% methanol in dichloromethaneas eluent. The desired fractions were concentrated to affordrac-(4bS,5R,6R,7S,7aR)-4-chloro-7a-(4-cyanophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamideas white solid. Yield: 0.35 g, 65% (racemic mixture). The enantiomerswere separated by chiral preparative HPLC [chiralpak IA (4.6×250) mm,5μ]. n-Hexane/IPA=70/30 (v/v); Peak 1 (84 mg), [α]_(D) +76.5° (c 0.4,CHCl₃), R_(t)=12.226 min, ee:98.08% MS (ESI) m/z 476.24 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 8.41 (s, 1H), 8.18 (s, 1H), 7.49 (d, J=8.4 Hz, 2H),7.34 (d, J=9.2 Hz, 2H), 7.08-7.01 (m, 2H), 6.96-6.93 (m, 3H), 6.14 (s,1H), 5.50 (d, J=6 Hz, 1H), 4.77 (t, J=4.8 Hz, 1H), 4.61 (d, J=13.6 Hz,1H), 4.35-4.31 (m, 1H), 2.80 (s, 3H), 2.50 (s, 3H). Peak-2 (Cpd. No.98F, 74 mg); MS (ESI) m/z 476.24 [M+1]⁺[α]_(D) −78.0° (c 0.4, CHCl₃),R_(t)=17.345 min, ee:97.02%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (s, 1H),8.18 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.34 (d, J=9.2 Hz, 2H), 7.08-7.01(m, 2H), 6.96-6.93 (m, 3H), 6.14 (s, 1H), 5.50 (d, J=6 Hz, 1H), 4.77 (t,J=4.8 Hz, 1H), 4.61 (d, J=13.6 Hz, 1H), 4.35-4.31 (m, 1H), 2.80 (s, 3H),2.50 (s, 3H).

Example 99Rac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 99F)

Synthesis of (4-methoxybenzyl)hydrazine hydrochloride (2)

To a solution of 1-(chloromethyl)-4-methoxybenzene (1, 50.0 g, 320 mmol)in ethanol (1200 ml), hydrazine hydrate (36.0 g, 777.3 mmol, 80% aqueoussolution) was added at 0° C. The reaction was stirred at 90° C. for 2 h.After completion the reaction mixture was concentrated under reducedpressure to give crude residue. Residue obtained was diluted withethanol and acidified with 6 N hydrogen chloride to pH ˜2. Theprecipitated solid was filtered and dried under vacuum to afford(4-methoxybenzyl) hydrazine hydrochloride (2) as yellow solid. Yield:50.0 g. The crude product was used as such in next step. MS (ESI) m/z153.1 [M+1]⁺.

Synthesis of (E)-1-(2-(4-methoxybenzyl)hydrazono)propan-2-one (3)

The solution of (4-methoxybenzyl) hydrazine hydrochloride (2, 20.0 g,106.0 mmol), and pyruvaldehyde (16.7 g, 260.0 mmol) in water (300 ml)was stirred at room temperature for 2 h. After completion, reactionmixture was diluted with dichloromethane and washed with cold water. Theorganic layer was separated and dried over anhydrous sodium sulphate,filtered and concentrated to afford(E)-1-(2-(4-methoxybenzyl)hydrazono)propan-2-one (3) as yellow solid.Yield: 18.9 g, 65.9%; MS (ESI) m/z 205.04[M−1]⁻.

Synthesis of1-(4-hydroxy-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)ethan-1-one (4)

The solution of (E)-1-(2-(4-methoxybenzyl)hydrazono)propan-2-one (3,18.0 g, 87.0 mmol) and glyoxal (7.8 g, 260.0 mmol) in water (100 ml) washeated at 100° C. for 3 h. After completion, reaction mixture wasdiluted with dichloromethane and washed with cold water. The organiclayer was separated and dried over anhydrous sodium sulphate, filteredand concentrated to give crude. The crude was purified by silica gelcolumn chromatography eluting with 10% ethyl acetate in hexanes. Thedesired fractions were concentrated to afford1-(4-hydroxy-1-(4-methoxybenzyl)-1H-pyrazol-3-yl) ethan-1-one (4) aslight yellow solid. Yield: 6.4 g, 28.9%; MS (ESI) m/z 244.9[M−1]⁻.

Synthesis of(E)-3-(4-bromophenyl)-1-(4-hydroxy-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)prop-2-en-1-one(5)

To a solution of1-(4-hydroxy-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)ethan-1-one (4, 3.0 g,12.19 mmol) in methanol (15 mL), sodium hydroxide (1.46 g, 36.5 mmol)was added followed by addition of 4-bromobenzaldehyde (2.24 g, 12.19mmol) and the reaction mixture was heated at 90° C. for 30 min. Aftercompletion, reaction mixture was cooled to room temperature and theprecipitated solid was filtered, washed with water and dried undervacuum to afford of(E)-3-(4-bromophenyl)-1-(4-hydroxy-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)prop-2-en-1-one(5) as yellow solid. Yield: 3.5 g, 70%; MS (ESI) m/z 411[M−1]⁻.

Synthesis of5-(4-bromophenyl)-6-hydroxy-2-(4-methoxybenzyl)pyrano[3,2-c]pyrazol-7(2H)-one(6)

To a solution of(E)-3-(4-bromophenyl)-1-(4-hydroxy-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)prop-2-en-1-one(5, 3.50 g, 8.49 mmol) in ethanol (20 mL), 10% aqueous sodium hydroxidesolution (23 mL, 59.4 mmol) was added followed by addition of hydrogenperoxide (6.7 mL, 59.4 mmol, 30%) at room temperature. The reactionmixture was stirred for 2 h (exotherm was observed). After completion,reaction mixture was cooled and neutralized with 6 M hydrogen chlorideto pH ˜7. The precipitated solid was filtered and dried under vacuum toafford 5-(4-bromophenyl)-6-hydroxy-2-(4-methoxybenzyl)pyrano[3,2-c]pyrazol-7(2H)-one (6) as brown solid. Yield: 2.0 g, 55.4%;MS (ESI) m/z 425.31[M−1]⁻.

Synthesis of rac-methyl(6S,7S,8R)-5-(4-bromophenyl)-8-hydroxy-2-(4-methoxybenzyl)-9-oxo-6-phenyl-5,6,7,8-tetrahydro-2H-5,8-methanooxepino[3,2-c] pyrazole-7-carboxylate (8)

A solution of 5-(4-bromophenyl)-6-hydroxy-2-(4-methoxybenzyl)pyrano[3,2-c]pyrazol-7(2H)-one (6, 8.0 g, 18.69 mmol) and methylcinnamate (7, 30.4 g, 187.1 mmol) in dichloromethane (200 mL),acetonitrile (100 mL) and methanol (100 mL) was placed in a UV reactorflask. The reaction mixture was irradiated with 400 watts UV light for 8h. After completion, the solvent was removed under reduced pressure andthe residue was purified over a plug of silica gel eluting the compoundwith 0-5% methanol in dichloromethane. The desired fractions wereconcentrated under reduced pressure to afford rac-methyl(6S,7S,8R)-5-(4-bromophenyl)-8-hydroxy-2-(4-methoxybenzyl)-9-oxo-6-phenyl-5,6,7,8-tetrahydro-2H-5,8-methanooxepino[3,2-c]pyrazole-7-carboxylate(8). Yield: 6.0 g, crude, MS (ESI) m/z 587.1[M−1]⁻.

Synthesis of rac-methyl(4aR,5S,6R,7aR)-4a-(4-bromophenyl)-7a-hydroxy-2-(4-methoxybenzyl)-7-oxo-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(9)

The crude rac-methyl(6S,7S,8R)-5-(4-bromophenyl)-8-hydroxy-2-(4-methoxybenzyl)-9-oxo-6-phenyl-5,6,7,8-tetrahydro-2H-5,8-methanooxepino[3,2-c]pyrazole-7-carboxylate(8, 6.00 g, crude) was suspended in methanol (50 mL) and treated withsodium methoxide (25% in methanol, 40 mL) and heated the mixture to 90°C. for 3 h. After completion, the solvent was removed under reducedpressure, diluted the mixture with ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover anhydrous sodium sulphate and concentrated under reduced pressureto afford rac-methyl(4aR,5S,6R,7aR)-4a-(4-bromophenyl)-7a-hydroxy-2-(4-methoxybenzyl)-7-oxo-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(9). Yield: 6.1 g, crude, MS (ESI) m/z 587.3[M−1]⁻

Synthesis of rac-methyl(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(10)

To a solution of rac-methyl(4aR,5S,6R,7aR)-4a-(4-bromophenyl)-7a-hydroxy-2-(4-methoxybenzyl)-7-oxo-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(9, 6.0 g, 10.2 mmol) in acetonitrile (80 mL) and acetic acid (6.1 mL,102.0 mmol) sodium triacetoxyborohydride (13.0 g, 61.2 mmol) was addedand resulting reaction mixture was stirred for 18 h at room temperature.After completion, the reaction mixture was partitioned between saturatedaqueous sodium bicarbonate solution and ethyl acetate. The organic layerwas separated, dried over anhydrous sodium sulphate and concentratedunder reduced pressure to get the crude product. The crude productobtained was purified by silica gel column chromatography eluting with2% methanol in dichloromethane. The desired fractions were concentratedto afford rac-methyl(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(10) as off white solid. Yield: 0.49 g, 8.3%; MS (ESI) m/z 591.36[M+1]⁺.

Synthesis ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylicacid (11)

To a solution of rac-methyl(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate(10, 0.47 g, 0.79 mmol) in methanol:tetrahydrofuran:water (3:2:1, 18mL), lithium hydroxide (0.33 g, 7.9 mmol) was added and the reaction wasstirred for 2 h at room temperature. After completion, the reactionmixture was cooled to 0° C. and acidified with 1 M hydrogen chloride topH ˜3. The precipitated solid was filtered and dried under vacuum toafford rac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylicacid (11) as white solid. Yield: 0.41 g, 89.4%, MS (ESI) m/z 577.09[M+1]⁺.

Synthesis ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(12)

To a solution ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylicacid (11, 0.4 g, 0.69 mmol) in dichloromethane (10 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.39 g,2.07 mmol), 1-hydroxybenzotriazole (0.32 g, 2.07 mmol) andN,N-diisopropylethylamine (0.7 mL, 4.14 mmol) were added at 0° C. andstirred the mixture for 5 minutes. Dimethylamine hydrochloride (0.28 g,3.48 mmol) was then added at same temperature and the reaction mixturewas stirred for 16 h at 40° C. After completion, reaction mixture wasdiluted with dichloromethane and washed with cold water. The organiclayer was separated and dried over anhydrous sodium sulphate, filteredand concentrated to give crude product. The crude product obtained waspurified by silica gel column chromatography eluting with 3% methanol indichloromethane. The desired fractions were concentrated to affordrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(12) as white solid. Yield: 0.26 g, 62.7%; MS (ESI) m/z 604.01 [M+1]⁺.

Synthesis ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 99F)

To a solution ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(12, 0.100 g, 0.16 mmol) in N,N-dimethylformamide (2.0 mL), zinc cyanide(0.11 g, 0.99 mmol) and zinc dust (0.002 g, 0.019 mmol) were added atroom temperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (2 mg, 0.003 mmol) andtris(dibenzylideneacetone)dipalladium (5 mg, 0.004 mmol) were added tothe reaction mixture and degassing was continued for another 5 min. Thereaction mixture was heated at 140° C. for 3 h. After completion, thereaction mixture was diluted with ethyl acetate and washed with coldwater. The organic layer was separated and dried over anhydrous sodiumsulphate, filtered and concentrated to give crude product. The crudeproduct was purified by silica gel column chromatography using 2-3%methanol in dichloromethane as eluent. The desired fractions wereconcentrated to affordrac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 99F) as white solid. Yield: 0.068 g, 74.4% (Racemic) MS (ESI)m/z 551.49 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.51 (d, J=8.4 Hz, 2H),7.40 (s, 1H), 7.33 (d, J=8.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 7.02-6.94(m, 3H), 6.88 (d, J=7.2 Hz, 2H), 6.81 (d, J=7.2 Hz, 2H), 5.69 (s, 1H),5.22-5.14 (m, 3H), 4.79 (t, J=6.9 Hz, 1H), 4.44 (d, J=13.4 Hz, 1H), 4.10(dd, J=13.4, 7.6 Hz, 1H), 3.72 (s, 3H), 3.21 (s, 3H), 2.74 (s, 3H).

Example 100 Rac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 100F)

Synthesis ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 100F)

To compoundrac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(1, 0.1 g, 0.18 mmol), trifluoroacetic acid (2 ml) was added at 0° C.and reaction mixture was heated at 100° C. for 2 h. After completion,reaction mixture was concentrated under reduced pressure to give crudeproduct, which was purified by preparative HPLC. The desired fractionswere concentrated to affordrac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 100F) as white solid. Yield: 0.020 g, 25.4% (racemic mixture);MS (ESI) m/z 431.24 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.54 (d, J=8.5Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 7.28 (s, 1H), 7.02-6.95 (m, 3H), 6.80(d, J=6.96 Hz, 2H), 5.67 (s, 1H), 4.85 (d, J=7.84 Hz, 1H), 4.44 (d,J=13.2 Hz, 1H), 4.06 (dd, J=13.2, 7.6 Hz, 1H), 3.20 (s, 3H), 2.73 (s,3H).

Example 101Rac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(methylsulfonyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 101F)

Synthesis ofrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-6-(methylsulfonyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(3)

To a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.36 mL, 2.37 mmol)in dimethyl sulfoxide (5.0 mL), copper(II) bromide (6.0 mg, 0.027 mmol)was added at room temperature in presence of air.Rac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(1, 0.18 g, 0.39 mmol) and sodium methanesulfinate (2, 0.404 g, 3.9mmol) in dimethyl sulfoxide (5.0 mL) were added drop wise to abovereaction mixture at room temperature in presence of air. The reactionmixture was stirred at room temperature for 1 h. After completion,(monitored by MS), the reaction mass was diluted with ethyl acetate andwashed with cold water. The organic layer was separated and dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure to affordrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-6-(methylsulfonyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(3). Yield: 0.1 g, crude; MS (ESI) m/z 528 [M−1]⁻.

Synthesis ofrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(methylsulfonyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 101F)

To a solution of sodium triacetoxyborohydride (0.24 g, 1.13 mmol) andrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-6-(methylsulfonyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(3, 0.1 g, 0.18 mmol) in acetonitrile (10 mL), acetic acid (0.1 mL, 1.81mmol) was added. The resulting mixture was stirred for 6 h at roomtemperature. After completion, reaction mixture was partitioned betweensaturated aqueous sodium bicarbonate solution and ethyl acetate. Theorganic layer was separated, dried over anhydrous sodium sulphate andconcentrated under reduced pressure to get the crude. The crude waspurified by Combi-flash (4.0 g, RediSep column) using 40% ethyl acetatein hexanes as eluent. The desired fractions were concentrated underreduced pressure to affordrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(methylsulfonyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 101F) as off white solid. Yield: 3.8 mg, 0.3%. MS (ESI) m/z532.13 [M+1]⁺; UPLC 99.5%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (s, 1H),8.05 (s, 1H), 7.26 (d, J=8.84 Hz, 2H), 7.19 (d, J=8.72 Hz, 2H),7.12-7.10 (m, 2H), 7.05-7.04 (m, 3H), 6.17 (bs, 1H), 6.07 (bs, 1H), 4.81(d, J=3.12 Hz, 1H), 4.75 (dd, J=4.0 Hz, 13.8 Hz, 1H), 4.40 (d, J=13.8Hz, 1H), 3.90 (s, 3H), 2.80 (s, 3H).

Example 1024-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(methylsulfonyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 102F)

Synthesis of 4-((4bS,5S, 6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(methylsulfonyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 102F)

To a solution ofrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(methylsulfonyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(1, 0.25 g, 0.47 mmol) in N,N-dimethylformamide (3.0 mL), zinc cyanide(0.081 g, 0.7 mmol) and zinc dust (0.003 g, 0.04 mmol) were added atroom temperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.008 g, 0.014 mmol) andtris(dibenzylideneacetone)dipalladium (0.012 g, 0.014 mmol) were addedto the reaction mixture and degassing was continued for another 5 min.The reaction mixture was heated at 150° C. for 2 h. After completion,the reaction was cooled to room temperature and passed through celitebed. The filtrate was diluted with ethyl acetate and washed with water.The organic layer was separated, dried over anhydrous sodium sulphateand concentrated under reduced pressure to get the crude. The crude waspurified by Combi-flash (12 g, RediSep column) using 70% ethyl acetatein hexanes as eluent. The desired fractions were concentrated underreduced pressure to affordrac-4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(methylsulfonyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 110 mg, 48.8%. MS (ESI) m/z 479.19 [M+1]⁺; UPLC98.5%; The enantiomers were separated by chiral preparative HPLC[chiralpak ID (4.6×250) mm] using n-Hexane/EtOH=40/60 (v/v) mobilephase. Peak 1 (Cpd. No. 102F, 27.0 mg); [α]_(D) +34.8° (c 0.25, CHCl₃);R_(t)=7.65 min, ee>99%; MS (ESI) m/z 479.17 [M+1]⁺; UPLC: 98.5%; ¹H NMR(400 MHz, DMSO-d₆) δ: 8.08 (s, 1H), 8.01 (s, 1H), 7.52 (d, J=8.64 Hz,2H), 7.44 (d, J=8.33 Hz, 2H), 7.14-7.12 (m, 2H), 7.05-7.00 (m, 3H), 6.17(d, J=6.5 Hz, 1H), 6.07 (s, 1H), 4.86-4.80 (m, 2H), 4.46 (d, J=13.4 Hz,1H), 3.88 (s, 3H), 2.85 (s, 3H). Peak-2 (20.0 mg); [α]_(D) −31.5° (c0.25, CHCl₃); R_(t)=12.5 min, ee>99%; MS (ESI) m/z 479.19 [M+1]⁺; UPLC:99.6%; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.08 (s, 1H), 8.00 (s, 1H), 7.52 (d,J=8.64 Hz, 2H), 7.45 (d, J=8.36 Hz, 2H), 7.14-7.12 (m, 2H), 7.04-7.02(m, 3H), 6.17 (d, J=6.5 Hz, 1H), 6.07 (s, 1H), 4.86-4.80 (m, 2H), 4.46(d, J=13.4 Hz, 1H), 3.88 (s, 3H), 2.85 (s, 3H).

Example 1034-((4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No.

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 0.80 g, 1.52 mmol) in dry tetrahydrofuran (20 mL) at 0° C., boranedimethyl sulphide complex (1.30 ml, 15.2 mmol) was added. The resultingmixture was stirred for 16 h at room temperature. After completion, thereaction mass was quenched with methanol at 0° C. and refluxed at 80° C.for 6 h. After completion, the reaction mass was concentrated to givecrude product. The crude product was purified by silica gel columnchromatography using 0-5% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 0.41 g, 56.7%; MS (ESI) m/z 511.17 [M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 103F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.4 g, 1.04 mmol) in N,N-dimethylformamide (10 mL), zinc cyanide(0.45 g, 3.92 mmol) and zinc dust (0.026 g, 0.39 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15minute. 1,1′-Bis(diphenylphosphino)ferrocene (0.021 g, 0.039 mmol) andtris(dibenzylideneacetone)dipalladium (0.035 g, 0.039 mmol) were addedto the reaction, degassed for additional 5 minute and heated the mixtureat 140° C. for 3 h. After completion, the reaction mass was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by silica gel column chromatographyusing 2-3% methanol in dichloromethane as eluent. The desired fractionswere concentrated to affordrac-4-((4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.220 g, 62.8% (racemic). MS (ESI) m/z 458.31[M+1]⁺. The enantiomers were separated by chiral preparative HPLC[chiralpak ID (4.6×250) mm, 5μ]. Peak 1 (43 mg), R_(t)=10.667 min,ee=99.24%, ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.96 (s, 1H), 7.49(d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.09-7.05 (m, 2H), 7.01-6.97(m, 3H), 5.73 (s, 1H), 4.48 (d, J=3.84 Hz, 1H), 3.87 (s, 3H), 3.78 (d,J=14.1 Hz, 1H), 3.19-3.12 (m, 1H), 2.20 (s, 6H), 1.97 (d, J=12.8 Hz,1H), 1.89 (s, 2H). Peak 2 (Cpd. No. 103F, 38 mg), [α]_(D) +25.0° (c0.26, CHCl₃), R_(t)=13.904 min, ee>97%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.04(s, 1H), 7.96 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz 2H),7.09-7.05 (m, 2H), 7.01-6.99 (m, 3H), 5.73 (s, 1H), 4.48 (d, J=3.96 Hz,1H), 3.87 (s, 3H), 3.78 (d, J=14 Hz, 1H), 3.19-3.16 (m, 1H), 2.20 (s,6H), 1.97 (d, J=12.8 Hz, 1H), 1.88 (s, 2H).

Example 104(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 104F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(2)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(7, 2.0 g, 3.78 mmol) in dry tetrahydrofuran (30 ml) at 0° C., boranedimethyl sulphide complex (3.59 mL, 37.87 mmol) was added drop wise overa period of 5 min. The reaction mass was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mass was quenched with methanol at 0° C. and heated to refluxfor 5 h. After completion, solvent was removed under reduced pressureand the residue was purified over a plug of silica gel eluting thecompound with 1-5% methanol in dichloromethane. The desired fractionswere concentrated under reduced pressure to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(8) as white solid. Yield: 1.2 g, 61.8%; MS (ESI) m/z 515.32 [M+1]⁺.

Synthesis of4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 104F)

To a solution ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(8, 1.2 g, 2.32 mmol) in N,N-dimethylformamide (48 mL), zinc cyanide(0.273 g, 2.32 mmol) and zinc dust (0.304 g, 4.65 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.025 g, 0.046 mmol) andtris(dibenzylideneacetone)dipalladium (0.064 g, 0.069 mmol) were addedto the reaction, degassed for additional 5 min and mixture was heated at130° C. for 4 h. After completion, the reaction mass was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by silica gel columnchromatography using 2-3% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 104F) as white solid. Yield: 0.49 g, 46.2% (racemic). MS (ESI)m/z 462.23 [M+1]⁺. The enantiomers were separated by chiral HPLC[chiralpak IA (4.6×250) mm, 5μ], n-hexane/EtOH 20/80 V/V.

Peak-1 (137 mg), [α]_(D) −110.4° (c 0.26, CHCl₃), R_(t)=4.580 min, ee:98.5% MS (ESI) m/z 462.23 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (d,J=1.60 Hz, 1H), 7.63 (d, J=1.68 Hz, 1H), 7.48 (d, J=8.42 Hz, 2H), 7.36(d, J=8.40 Hz, 2H), 7.15-6.98 (m, 5H), 6.12 (s, 1H), 5.41 (bs, 1H), 4.45(s, 1H), 3.93 (d, J=13.90 Hz, 1H), 3.24 (bs, 1H), 2.66 (s, 1H), 2.59 (s,1H), 2.25 (s, 6H). Peak-2 (133 mg), [α]_(D) +105.4° (c 0.25, CHCl₃),R_(t)=12.693 min, ee: 99.9%, MS (ESI) m/z 462.23 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.18 (d, J=1.60 Hz, 1H), 7.63 (d, J=1.68 Hz, 1H), 7.48(d, J=8.42 Hz, 2H), 7.36 (d, J=8.40 Hz, 2H), 7.15-6.98 (m, 5H), 6.12 (s,1H), 5.41 (bs, 1H), 4.45 (s, 1H), 3.93 (d, J=13.90 Hz, 1H), 3.24 (bs,1H), 2.66 (s, 1H), 2.59 (s, 1H), 2.25 (s, 6H).

Example 1055aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-3-carbonitrile(Cpd. No. 105F)

Synthesis of5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-3-carbonitrile(Cpd. No. 105F)

To a solution ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(1, 0.4 g, 0.77 mmol) in N,N-dimethylformamide (5.0 mL), zinc cyanide(0.099 g, 0.85 mmol) and zinc dust (0.099 g, 1.55 mmol) were added atroom temperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.011 g, 0.015 mmol),tris(dibenzylideneacetone)dipalladium (0.021 g, 0.023 mmol) were addedto the reaction and degassing was continued for another 5 min. Thereaction mixture was heated at 140° C. for 3 h. After completion, thereaction was cooled to room temperature and passed through celite bed.The filtrate was diluted with ethyl acetate and washed with water. Theorganic layer was separated, dried over sodium sulphate and concentratedunder reduced pressure to get the crude. The crude was purified bycombi-flash (12 g, RediSep column), using 0-15% methanol indichloromethane as eluent. The desired fractions were concentrated underreduced pressure. The Compound was again repurified by reverse phasepreparative HPLC. The desired fractions were lyophilized to giverac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-3-carbonitrileas white solid. The enantiomers were separated by chiral preparativeHPLC [chiralpak IA (4.6×250) mm]; 0.1% TEA in n-Hexane/IPA=80/20 (v/v);Yield: 120 mg, 34%; Peak 1 (Cpd. No. 105F, 7 mg), [α]_(D) −71.9° (c0.26, CHCl₃), R_(t)=22.203, ee>99%; MS (ESI) m/z 453.29 [M+1]⁺; UPLC:98.48%; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.60 (s, 1H), 7.96 (s, 1H), 7.48(d, J=8.3 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 7.11-7.00 (m, 5H), 6.33 (s,1H), 4.48 (d, J=2.84 Hz, 1H), 3.96 (d, J=13.8 Hz, 1H), 3.25 (m, 1H),2.66-2.49 (m, 1H), 2.21 (s, 6H), 2.00-1.97 (d, J=11.0 Hz, 1H). Peak 2 (4mg), [α]_(D) +21.9° (c 0.266, CHCl₃), R_(t)=34.931, ee>98%; MS (ESI) m/z453.29 [M+1]⁺; UPLC: 99.54%; 1H NMR (400 MHz, DMSO-d₆) δ: 8.60 (d,J=1.32 Hz, 1H), 7.96 (d, J=1.28 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.35(d, J=8.4 Hz, 2H), 7.11-6.98 (m, 5H), 6.32 (s, 1H), 5.46 (brs, 1H), 4.48(d, J=3.3 Hz, 1H), 3.96 (d, J=13.9 Hz, 1H), 3.41-3.25 (m, 1H), 2.60-2.4(m, 1H), 2.20 (s, 6H), 1.98 (d, J=10.3 Hz, 1H).

Example 106(4bS,5R,6S,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 106F)

Synthesis of 4-(difluoromethyl)benzaldehyde (2)

To a solution of 1-bromo-4-(difluoromethyl)benzene (1, 35.0 g, 169.08mmol) in dry tetrahydrofuran (300 mL), n-butyllithium in hexane (2.5 M,67.0 mL, 169.08 mmol) was added drop wise over a period of 30 min at−78° C. The reaction mass was stirred for 1 h at −78° C. andN,N-dimethylformamide (38.48 mL, 507.24 mmol) was added at sametemperature and the reaction was further stirred at −78° C. for 1 h.After completion, the reaction mixture was brought to 0° C. and treatedwith saturated ammonium chloride solution and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to get the crude. Thecrude was purified by Combi-flash (40 g, RediSep column) using 2% ethylacetate in hexanes as eluent. The desired fraction were concentratedbelow 30° C. under reduced pressure to afford4-(difluoromethyl)benzaldehyde (2) as light yellow liquid (highlyunstable). Yield: 17.0 g, 64%; MS (ESI) m/z poor ionization.

Synthesis of (E)-3-(4-(difluoromethyl)phenyl)-1-(3-hydroxy-5-methoxypyridin-4-yl) prop-2-en-1-one (4)

To a solution of 1-(3-hydroxy-5-methoxypyridin-4-yl)ethan-1-one (3, 12.6g, 75.4 mmol) in methanol (50 mL), sodium hydroxide (6.03 g, 150.0 mmol)and 4-(difluoromethyl)benzaldehyde (2, 11.7 g, 75.4 mmol) were added at0° C. and the reaction mixture was stirred at room temperature for 1 h.After completion, the reaction mixture was cooled, water was added thenneutralized to pH˜7 with 6M hydrogen chloride at 0° C., obtained solidwas filtered, washed with excess water and dried under vacuum to afford(E)-3-(4-(difluoromethyl)phenyl)-1-(3-hydroxy-5-methoxypyridin-4-yl)prop-2-en-1-one (4) as yellowsolid. Yield: 20.2 g, MS (ESI) m/z 304.13[M−1]⁻.

Synthesis of 2-(4-(difluoromethyl)phenyl)-3-hydroxy-5-methoxy-4H-pyrano[2,3-c]pyridin-4-one (5)

To a solution of(E)-3-(4-(difluoromethyl)phenyl)-1-(3-hydroxy-5-methoxypyridin-4-yl)prop-2-en-1-one(4, 20.2 g, 65.5 mmol) in methanol (200 mL), 10% sodium hydroxide (65.6mL, 163.9 mmol) was added followed by addition of hydrogen peroxide(18.6 mL, 163.9 mmol, 30%) at 0° C. The reaction mass was stirred for 45min at 0° C. After completion the reaction mixture was and neutralizedwith 6 M hydrogen chloride to pH ˜7. The solvent was distilled off andprecipitated solid was filtered and dried under vacuum to afford2-(4-(difluoromethyl)phenyl)-3-hydroxy-5-methoxy-4H-pyrano[2,3-c]pyridin-4-one (5) as paleyellow solid. Yield: 5.5 g, 26%; MS (ESI) m/z 318.23[M−1]⁻.

Synthesis of rac-methyl(2S,3S,4S,5R)-2-(4-(difluoromethyl)phenyl)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(7,7a)

A solution of 2-(4-(difluoromethyl)phenyl)-3-hydroxy-5-methoxy-4H-pyrano[2,3-c]pyridin-4-one (5, 5.5 g,17.24 mmol) and methyl cinnamate (6, 28.0 g, 172.4 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedfor 16 h under 400 watts UV light. After completion, the solvent wasremoved under reduced pressure and the crude was purified by Combi-flash(40 g, RediSep column) using ethyl acetate as eluent. The desiredfractions were concentrated under reduced pressure to afford rac-methyl(2S,3S,4S,5R)-2-(4-(difluoromethyl)phenyl)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(7,7a) as brown solid. Yield: 6.0 g, crude.

Synthesis of rac-methyl(4bR,6R,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8)

The crude rac-methyl(2S,3S,4S,5R)-2-(4-(difluoromethyl)phenyl)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(7,7a, 6.0 g) was suspended in methanol (60 mL) and treated with sodiummethoxide (25% in methanol, 60 mL) and heated the mixture to 90° C. for3 h. After completion, the solvent was removed under reduced pressureand mixture was diluted with ammonium chloride solution and extractedwith ethyl acetate. The organic phase was separated, dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure to afford rac-methyl(4bR,6R,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8) as brown solid. Yield: 5.3 g, crude.

Synthesis of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(9)

To a solution of sodium triacetoxyborohydride (14.0 g, 66.1 mmol),rac-methyl(4bR,6R,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8, 5.3 g, 11 mmol) in acetonitrile (50 mL), acetic acid (6.6 mL, 110.0mmol) was added. The resulting mixture was stirred at room temperaturefor 4 h. After completion, reaction mixture was partitioned betweensaturated aqueous sodium bicarbonate solution and ethyl acetate. Theorganic layer was separated, dried over sodium sulphate and concentratedunder reduced pressure to get the crude. The crude was purified byCombi-flash (40 g, RediSep) using 90% ethyl acetate in hexanes aseluent. The desired fractions were concentrated under reduced pressureto afford rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(9) as off white solid. Yield: 2.35 g, 44%; MS (ESI) m/z 482.22 [M−1]⁻.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (10)

To a solution of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(9, 2.35 g, 4.86 mmol) in methanol and water (3:1, 24 mL), lithiumhydroxide (1.16 g, 48.6 mmol) was added and the reaction was stirred atroom temperature for 1 h. After completion, methanol was distilled offand reaction mass was cooled to 0° C. and acidified with 1 M hydrogenchloride to pH ˜6. The precipitated solid was filtered and dried undervacuum to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (10) as off white solid. Yield: 1.97 g, 93%; MS (ESI) m/z468.31[M−1]⁻.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(11)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (10, 0.6 g, 1.27 mmol) in dichloromethane (20 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.73 g,3.83 mmol), 1-hydroxybenzotriazole (0.518 g, 3.83 mmol) andN,N-diisopropylethylamine (1.34 mL, 7.67 mmol) were added at 0° C. andstirred the mixture for 5 min. Dimethylamine hydrochloride (0.518 g,6.39 mmol) was then added at same temperature and the mixture wasstirred for 16 h at 40° C. After completion, reaction mass was dilutedwith dichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by Combi-flash (12 g,RediSep) using 90% ethyl acetate in hexanes as eluent. The desiredfractions were concentrated under reduced pressure to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(11) as off white solid. Yield: 0.59 g, 93%; MS (ESI) m/z 497.42 [M+1]⁺.

Synthesis of(4bS,5R,6S,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 106F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(11, 0.59 g, 1.18 mmol) in tetrahydrofuran (15 mL), borane dimethylsulphide (1.13 mL 11.8 mmol) was added at 0° C. and stirred the mixturefor 2 h at 60° C. After completion, reaction mass was quenched withmethanol (5.0 mL) and again heated for 10 h at 60° C. The reactionmixture was concentrated under reduced pressure to get the crude. Thecrude was purified by combi-flash (12 g, RediSep) using 20% methanol indichloromethane as eluent. The desired fractions were concentrated toaffordrac-(4bS,5R,6S,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diolas white solid. Yield: 75 mg, 13%. The enantiomers were separated bychiral preparative HPLC [chiralpak IA (4.6×250) mm] Mobile phase: 0.1%TEA in n-Hexane/EtOH=85/15 (v/v). Peak 1 (46 mg), [α]_(D) +9.6° (c0.250, CHCl₃), R_(t)=14.72, ee>99% MS (ESI) m/z 483.28 [M+1]⁺ UPLC:98.5%. 1H NMR (400 MHz, DMSO-d₆) δ: 8.04 (s, 1H), 7.95 (s, 1H), 7.33 (d,J=8.0 Hz, 2H), 7.21 (d, J=8.1 Hz, 2H), 7.07-7.03 (m, 2H), 6.97-6.90 (m,3H), 6.83 (t, J=55.9 Hz, 1H), 5.64 (s, 1H), 4.52 (d, J=3.7 Hz, 1H), 3.87(s, 3H), 3.76 (d, J=14.0 Hz, 1H), 3.19-3.15 (m, 1H), 2.65-2.61 (m, 2H),2.22 (s, 6H), 1.98 (s, 1H). Peak 2 (Cpd. No. 106F, 29 mg), [α]_(D) −2.4°(c 0.25, CHCl₃), R_(t)=26.39, ee>99% MS (ESI) m/z 483.33 [M+1]⁺, UPLC:99.3%. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.03 (s, 1H), 7.95 (s, 1H), 7.32 (d,J=8.2 Hz, 2H), 7.22 (d, J=8.1 Hz, 2H), 7.07-7.03 (m, 2H) 6.97-6.95 (m,3H), 6.83 (t, J=55.8 Hz, 1H), 5.641 (s, 1H), 4.51 (d, J=4.2 Hz, 1H),3.87 (s, 3H), 3.76 (d, J=14.1 Hz, 1H), 3.18 (t, J=11.0 Hz, 1H),2.58-2.50 (m, 2H), 2.20 (s, 6H), 1.95 (d, J=4.2 Hz, 1H).

Example 107(4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 107F)

Synthesis of(E)-1-(3-hydroxy-5-methoxypyridin-4-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one (3)

To a solution of 1-(3-hydroxy-5-methoxypyridin-4-yl) ethan-1-one (1,10.0 g, 59.8 mmol) and 4-(trifluoromethyl)benzaldehyde (2, 10.41 g, 59.8mmol) in methanol (50 mL), sodium hydroxide (7.17 g, 179.4 mmol) wasadded and the mixture was heated to reflux for 30 min. After completion,the reaction mass was cooled to room temperature, the solvent methanolwas distilled off under reduced pressure and the residue was neutralizedwith 1N hydrochloric acid up to pH-7 at 0° C. The precipitated solid wasfiltered, washed with water, n-pentane and dried under vacuum to afford(E)-1-(3-hydroxy-5-methoxypyridin-4-yl)-3-(4-(trifluoromethyl) phenyl)prop-2-en-1-one (3) as yellow solid. Yield: 16.1 g, 83.0%; MS (ESI) m/z324.22[M+1]⁺.

Synthesis of 3-hydroxy-5-methoxy-2-(4-(trifluoromethyl)phenyl)-4H-pyrano[2,3-c]pyridin-4-one (4)

To a solution of(E)-1-(3-hydroxy-5-methoxypyridin-4-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(3, 15.0 g, 46.4 mmol) in ethanol (150 mL) at 0° C., sodium hydroxide(2.22 g, 55.68 mmol) was added followed by the addition of 30% aqueoushydrogen peroxide (36.80 mL, 324.8 mmol). The reaction mass was stirredfor 30 min at 60° C. After completion, the reaction mass was cooled andneutralized by the addition of 6 M hydrochloric acid to pH ˜7. The solidobtained was filtered, washed with cold ethanol, pentane and dried undervacuum to afford 3-hydroxy-5-methoxy-2-(4-(trifluoromethyl)phenyl)-4H-pyrano[2,3-c]pyridin-4-one (4) as pale yellow solid. Yield:3.2 g, 20%; MS (ESI) m/z 338.09[M+1]⁺.

Synthesis of rac-methyl(3S,4S,5R)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2-(4-(trifluoromethyl)phenyl)-2,3,4, 5-tetrahydro-2, 5-methanooxepino[2,3-c]pyridine-4-carboxylate (6)

A solution of 3-hydroxy-5-methoxy-2-(4-(trifluoromethyl)phenyl)-4H-pyrano[2,3-c]pyridin-4-one (4, 3.2 g, 9.48 mmol) and methylcinnamate (5, 15.38 g, 94.88 mmol) in dichloromethane (200 mL),acetonitrile (100 mL) and methanol (100 mL) was placed in a UV reactorflask. The reaction mixture was irradiated under 400 watts UV light for24 h. After completion, solvent was removed under reduced pressure andthe residue was purified over a plug of silica gel eluting the compoundwith 5% methanol in dichloromethane. The desired fractions wereconcentrated under reduced pressure to afford rac-methyl(3S,4S,5R)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(6) as brown solid. Yield: 3.5 g, 74%; MS (ESI) m/z 499.39[M−1]⁻.

Synthesis of rac-methyl (4bR,6R,7S,7aR)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7)

A solution of rac-methyl(3S,4S,5R)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(6, 3.5 g, 7.0 mmol) was suspended in methanol (35 mL) and treated with25% sodium methoxide in methanol (7.0 mL). The reaction was heated at80° C. for 4 h. After completion, the solvent was removed under reducedpressure. The crude was diluted with ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and concentrated under reduced pressure to affordrac-methyl(4bR,6R,7S,7aR)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7) as brown solid. Yield: 3.2 g, crude; MS (ESI) m/z 500.16[M+1]⁺.

Synthesis of rac-methyl(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8)

A solution of rac-methyl(4bR,6R,7S,7aR)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7, 3.2 g, 6.40 mmol) in acetonitrile (60 mL) was cooled at 0° C.,acetic acid (3.84 g, 64.07 mmol) and sodium triacetoxyborohydride (8.14g, 38.44 mmol) were added. The resulting mixture was stirred for 12 h atroom temperature. After completion, the reaction mixture was partitionedbetween saturated aqueous sodium bicarbonate solution and ethyl acetate.The organic layer was separated and dried over anhydrous sodiumsulphate, filtered and concentrated to give crude. The crude waspurified by silica gel column chromatography eluting with 2-3% inmethanol in dichloromethane. The desired fractions were concentrated toafford rac-methyl(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8) as white solid. Yield: 1.2 g, 38.0%; MS (ESI) m/z 502.19[M+1]⁺.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (9)

To a solution of rac-methyl(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8, 1.2 g, 2.39 mmol) in methanol, tetrahydrofuran and water (2:1:1, 12mL), lithium hydroxide (0.574 g, 23.9 mmol) was added and the reactionwas stirred for 6 h at room temperature. After completion, the reactionmass was concentrated and cooled to 0° C. and acidified with 1 Mhydrochloric acid to pH ˜2-3. The precipitated solid was filtered anddried under vacuum to affordrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (9) as off white solid. Yield: 0.90 g, 80%; MS (ESI) m/z 488.37[M+1]+.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(10)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (9, 0.9 g, 1.84 mmol) in dichloromethane (18 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.859 g, 5.53 mmol),hydroxybenzotriazole (0.846 g, 5.53 mmol) and N,N-diisopropylethylamine(1.82 mL, 11.04 mmol) were added and the mixture was stirred for 5 min.Dimethylamine hydrochloride (0.750 g, 9.2 mmol) was then added at thesame temperature and the mixture was stirred for 16 h at roomtemperature. After completion, the reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel column chromatography eluting with 2-3% methanol indichloromethane. The desired fractions were concentrated to affordrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(10) as off white solid; Yield: 0.60 g, 64%; MS (ESI) m/z 515.22 [M+1]+.

Synthesis of(4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 107F)

To a solutionrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(10, 0.6 g, 1.16 mmol) in tetrahydrofuran (12 mL), boranedimethylsulfide (1.10 ml, 11.66 mol) was added at 0° C. The reactionmixture was stirred at room temperature for 4.0 h. After completion,reaction mass was quenched with methanol at 0° C., then refluxed at 70°C. for 36 h The solvents were concentrated to give crude product. Thecrude product was purified by silica gel column chromatography elutingwith 5-10% in methanol in dichloromethane. The desired fractions wereconcentrated to affordrac-(4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diolas white solid; Yield: 0.310 g, 53% (racemic mixture), MS (ESI) m/z501.27 [M+1]⁺. The enantiomers were separated by chiral preparative HPLC[chiralpak IA (4.6×250)mm, 5μ] 0.1% diethyl amine inn-hexane/isopropanol 70/30 v/v; Peak 1 (42 mg), [α]_(D) +34.1° (c 0.3,CHCl₃), R_(t)=7.587 min, ee=99.78%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (s,1H), 7.96 (s, 1H), 7.42-7.37 (m, 4H), 7.08 (t, J=7.76 Hz, 2H), 7.00 (d,J=7.32 Hz, 2H), 5.70 (s, 1H), 5.14 (d, J=1.72 Hz, 1H), 4.51 (s, 1H),3.88 (s, 3H), 3.79 (d, J=13.92 Hz, 1H), 3.20 (d, J=21.16 Hz 1H), 2.21(s, 6H), 1.99 (s, 2H); Peak 2 (Cpd. No. 107F, 65 mg), [α]_(D) −53.2° (c0.27, CHCl₃), R_(t)=15.337 min, ee=99.60%; ¹H NMR (400 MHz, DMSO-d₆) δ8.04 (s, 1H), 7.96 (s, 1H), 7.41-7.36 (m, 4H), 7.07 (t, J=7.76 Hz, 2H),7.00 (d, J=7.32 Hz, 2H), 5.70 (s, 1H), 5.14 (s, 1H), 4.51 (d, J=3.16,1H), 3.87 (s, 3H), 3.87 (d, J=14.04 Hz, 1H), 3.16 (s, 1H), 2.20 (s, 6H),1.99 (d, J=9.4 Hz, 2H).

Example 108(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 108F)

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(2)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (1, 0.47 g, 1.00 mmol) in dichloromethane (15 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.576 g, 3.00 mmol),hydroxybenzotriazole (0.46 g, 3.00 mmol) and N,N-diisopropylethylamine(0.776 g, 6.00 mmol) were added and the mixture was stirred for 5 min.Dimethylamine hydrochloride (0.408 g, 5.0 mmol) was then added at thesame temperature and the reaction was stirred for 16 h at roomtemperature. After completion, the reaction mass was diluted withdichloromethane and washed with water. The organic layer was separatedand dried over anhydrous sodium sulphate, filtered and concentrated togive crude. The crude was purified by Combi-flash (4.0 g, RediSep) using3% methanol in dichloromethane as eluent. The desired fractions wereconcentrated to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(2) as light yellow solid. Yield: 0.35 g, 70%; MS (ESI) m/z 501.13[M+1]⁺.

Synthesis of(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 108F)

To a solution of rac-(5aR,6S,7R,8R,8aS)3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(2, 0.35 g, 0.6796 mmol) in dry tetrahydrofuran (6.0 ml) at 0° C.,borane dimethyl sulphide complex (0.66 mL, 6.796 mmol) was added at 0°C. The reaction mixture was heated at 60-70° C. for 5 h. Aftercompletion, the reaction mixture was quenched with methanol at 0° C. andagain heated for 10 h at 60° C. The solvent was removed under reducedpressure and the residue was purified by Combi-flash (4.0 g, RediSepcolumn) using 5% methanol in dichloromethane as eluent. The desiredfraction were concentrated under reduced pressure to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diolas white solid. Yield: 80 mg, 23.53%; MS (ESI) m/z 487.15 [M+1]⁺, UPLC:98.5%. The enantiomers were separated by chiral preparative HPLC[chiralpak IA (4.6×250) mm]; n-Heaxane/EtOH=75/25 (v/v); Peak 1 (Cpd.No. 108F, 2.2 mg); R_(t)=7.69, ee>99%; MS (ESI) m/z 487.22 [M+1]⁺; UPLC:98.6%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 1H), 7.60 (s, 1H), 7.31 (d,J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.11-6.96 (m, 5H), 6.82 (t,J=55.6 Hz, 1H), 6.00 (s, 1H), 4.47 (s, 1H), 3.89 (d, J=13.8 Hz, 1H),2.73-2.61 (m, 2H), 2.12 (s, 6H), 2.00 (d, J=12.6 Hz, 1H), 1.90 (s, 1H).Peak-2 (2.1 mg); R_(t)=19.71, ee>95%; MS (ESI) m/z 487.23 [M+1]⁺; UPLC:99.0%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 1H), 7.61 (s, 1H), 7.31 (d,J=7.9 Hz, 2H), 7.22 (d, J=7.9 Hz, 2H), 7.06-6.99 (m, 5H), 6.83 (t,J=57.1 Hz, 1H), 6.02 (S, 1H), 4.47 (s, 1H), 3.89 (d, J=14.5 Hz, 1H),2.70-2.61 (m, 2H), 2.23 (s, 6H), 2.02 (bs, 1H), 1.90 (s, 1H).

Example 109(5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 109F)

Synthesis of(5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6, 7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 109F)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(1, 0.20 g, 0.386 mmol) in tetrahydrofuran (5 mL), borane dimethylsulphide (0.36 mL 3.86 mmol) was added at 0° C. and stirred the mixturefor 3 h at 60° C. After completion, the reaction mixture was quenchedwith methanol (3.0 mL) and again heated for 10 h at 60° C. The reactionmixture was concentrated to give crude. The crude was purified byCombi-flash (12.0 g, RediSep column) using 20% methanol indichloromethane as eluent. The desired fractions were concentrated toaffordrac-(5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diolas off white solid. Yield: 32 mg, 16%. The enantiomers were separated bychiral preparative HPLC [chiralpak IA (4.6×250) mm] usingn-Hexane/EtOH=70/30 (v/v) mobile phase. Peak 1 (Cpd. No. 109F, 17 mg),[α]_(D) −93.2° (c 0.25, CHCl₃), R_(t)=6.12, ee>99%. MS (ESI) m/z 505.19[M+1]+, UPLC: 97.06%. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.18 (d, J=1.8 Hz,1H), 7.64 (d, J=1.8 Hz, 1H), 7.41-7.36 (m, 4H), 7.09-6.97 (m, 5H), 6.09(s, 1H), 5.38 (bs, 1H), 4.47 (d, J=3.3 Hz, 1H), 3.92 (d, J=14.0 Hz, 1H),3.21 (m, 1H), 2.66 (m, 1H), 2.26 (s, 6H), 2.05 (m, 1H). Peak 2 (11 mg),[α]_(D)+99.1° (c 0.25, CHCl₃), R_(t)=12.18, ee>99%. MS (ESI) m/z 505.19[M+1]⁺, UPLC: 97.92%. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.18 (d, J=1.84 Hz,1H), 7.64 (d, J=1.8 Hz, 1H), 7.41-7.38 (m, 4H), 7.09-6.96 (m, 5H), 6.09(s, 1H), 5.34 (bs, 1H), 4.47 (d, J=3.7 Hz, 1H), 3.92 (d, J=14.0 Hz, 1H),3.23 (m, 1H), 2.61 (d, J=9.2 Hz, 1H), 2.29 (s, 6H), 2.02-2.00 (m, 1H).

Example 1104-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(morpholinomethyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 110F)

Synthesis ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(morpholino)methanone(3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.2 g, 2.40 mmol) in dichloromethane (12 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.37 g,7.22 mmol), 1-hydroxybenzotriazole (0.97 g, 7.22 mmol) andN,N-diisopropylethylamine (2.21 mL, 12.12 mmol) were added at 0° C. andstirred the mixture for 5 minutes. Morpholine (2, 0.63 g, 7.20 mmol) wasadded at same temperature and the mixture was stirred for 16 h at 40° C.After completion, reaction mass was diluted with dichloromethane andwashed with cold water. The organic layer was separated and dried overanhydrous sodium sulphate, filtered and concentrated to give crude. Thecrude was purified by silica gel column chromatography eluting with 0-4%methanol in dichloromethane. The desired fractions were concentrated toaffordrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(morpholino)methanone(3) as white solid. Yield: 0.91 g, 66%; MS (ESI) m/z 567 [M+1]⁺.

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(morpholinomethyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4)

To a solution ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(morpholino)methanone(3, 0.8 g, 1.41 mmol) in dry tetrahydrofuran (20 mL) at 0° C., boranedimethyl sulphide complex (1.1 ml, 14.2 mmol) was added. The resultingmixture was stirred for 16 h at room temperature. After completion, thereaction mass was quenched with methanol at 0° C. and refluxed at 80° C.for 6 h. After completion, the reaction mass was concentrated to givecrude. The crude was purified by silica gel column chromatography using0-5% methanol in dichloromethane as eluent. The desired fractions wereconcentrated torac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(morpholinomethyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as white solid. Yield: 0.65 g, 80%; MS (ESI) m/z 553.17 [M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(morpholinomethyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 110F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(morpholinomethyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 0.6 g, 1.00 mmol) in N,N-dimethylformamide (10 mL), zinc cyanide(0.76 g, 6.52 mmol) and zinc dust (0.07 g, 0.12 mmol) were added at roomtemperature and the reaction mixture was degassed with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.006 g, 0.02 mmol) andtris(dibenzylideneacetone)dipalladium (0.003 g, 0.003 mmol) were addedto the reaction, degassed for additional 5 min and heated the mixture at140° C. for 3 h. After completion, the reaction mass was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by silica gel column chromatographyusing 3-4% methanol in dichloromethane as eluent. The desired fractionswere concentrated to affordrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(morpholinomethyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.30 g, 55% (racemic mixture). The enantiomerswere separated by chiral preparative chiral HPLC [chiralpak IA (4.6×250)mm, 5μ], n-Hexane/EtOH=30/70 v/v. Peak-1 (Cpd. No. 110F, 69 mg), [α]_(D)−4.0° (c 0.45, CHCl₃), R_(t)=5.548 min, ee>99.88%, ¹H NMR (400 MHz,DMSO-d₆) δ 8.04 (s, 1H), 7.96 (s, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.38 (d,J=8.0 Hz 2H), 7.09-7.00 (m, 5H), 5.70 (s, 1H), 5.10 (d, J=4.4 Hz, 1H),4.50 (s, 1H), 3.88 (s, 3H), 3.81 (d, J=14.0 Hz, 1H), 3.61 (bs, 4H), 3.31(bs, 1H), 2.62-2.50 (m, 4H), 2.33 (bs, 1H), 2.09 (d, J=12.0 Hz, 1H); MS(ESI) m/z 458.31 [M+1]⁺; Peak-2 (60 mg), [α]_(D) +4.3° (c 0.28, CHCl₃),R_(t)=8.285 min, ee>95.22%, ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (s, 1H),7.96 (s, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.38 (d, J=8.0 Hz 2H), 7.09-7.00(m, 5H), 5.70 (s, 1H), 5.10 (d, J=4.4 Hz, 1H), 4.50 (s, 1H), 3.88 (s,3H), 3.81 (d, J=14.0 Hz, 1H), 3.61 (bs, 4H), 3.31 (bs, 1H), 2.62-2.50(m, 4H), 2.33 (bs, 1H), 2.09 (d, J=12.0 Hz, 1H); MS (ESI) m/z 458.31[M+1]⁺.

Example 111Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 111F)

Synthesis of rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 111F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.0 g, 2.0 mmol) in N,N-dimethylformamide (20 mL),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (2.29 g, 6.0 mmol) andN,N-diisopropylethylamine (1.8 ml, 10.0 mmol) were added at 0° C. andstirred the mixture for 5 min. 2,2-Difluoroethan-1-amine hydrochloride(2, 0.39 g, 3.0 mmol) was then added and the reaction mixture wasstirred for 4 h at room temperature. After completion, reaction mass wasdiluted with ethylacetate and washed with cold water. The organic layerwas dried over anhydrous sodium sulphate, filtered and concentrated togive crude. The crude was purified by Combi-flash (12 g, RediSep column)using 3% methanol in dichloromethane as eluent. Further purification wasdone on reverse phase preperative HPLC. The desired fractions werelyophilized to afford rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 111F) as brown solid. Yield: 0.6 g, 54%; MS (ESI) m/z 575.25[M+1]⁺. UPLC: 99.64%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 1H), 8.00 (s,1H), 7.20 (d, J=8.5 Hz, 2H), 7.09-7.01 (m, 4H), 6.97 (d, J=7.01 Hz, 1H),6.91 (d, J=7.4 Hz, 2H), 6.56-6.29 (m, 1H), 5.74 (s, 1H), 5.22 (d, J=5.5Hz, 1H), 4.79 (t, J=5.4 Hz, 1H), 4.45 (d, J=10.0 Hz, 1H), 4.24 (dd,J=5.0 Hz, 13.6 Hz, 1H), 3.80 (s, 3H), 3.68-3.56 (m, 2H), 3.38 (s, 3H).

Example 1124-((4bS,5R,6S,7S,7aR)-6-(((2,2-difluoroethyl)(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 112F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2,2-difluoroethyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 0.6 g, 1.0 mmol) in tetrahydrofuran, borane dimethylsulfide (1.0 ml,10.0 mmol) was added at 0° C. The reaction mixture was heated at 60° C.for 5 h. After completion, reaction mass was quenched with methanol at0° C. and then heated at 80° C. for 6 h. The solvents were concentratedand compound was dried to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2,2-difluoroethyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as brown solid. Yield: 0.55 g, 95%; MS (ESI) m/z 559.57[M−1]⁻, UPLC:89.48%.

Synthesis of 4-((4bS,5R,6S,7S,7aR)-6-(((2,2-difluoroethyl)(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 112F)

To a mixture ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2,2-difluoroethyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.55 g, 0.98 mmol) in N,N-dimethylformamide (5.0 mL) at roomtemperature, zinc cyanide (690 mg, 5.89 mmol) and zinc dust (13 mg, 0.19mmol) were added at room temperature and degassed the mixture with argonfor 15 min. 1,1′-Bis(diphenylphosphino) ferrocene (16.0 mg, 0.029 mmol)and tris(dibenzylideneacetone)dipalladium (27.0 mg, 0.029 mmol) wereadded to the reaction mixture and degassing was continued for another 5min. The reaction mixture was heated at 140° C. for 6 h. Aftercompletion, the reaction was cooled to room temperature and passedthrough celite bed. The filtrate was concentrated and treated withice-cold water, the solid precipitated was filtered. The solid obtainedwas purified by Combi-flash (12 g, RediSep column) using 30% ethylacetate in hexanes as eluent. The crude was submitted for reverse phaseprep HPLC. The desired fractions were lyophilized to affordrac-4-((4bS,5R,6S,7S,7aR)-6-(((2,2-difluoroethyl)(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. The enantiomers were separated by chiral preparativeHPLC [chiralpak IB (4.6×250) mm] using 0.1% TEA in n-Hexane/IPA=80/20(v/v) Mobile phase. Yield: 0.12 g, 23%, Peak 1 (49 mg), [α]_(D) +48.8°(c 0.24, CHCl₃), R_(t)=9.414 min, ee>99%. MS (ESI) m/z 508.29 [M+1]⁺;UPLC: 99.36%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (s, 1H), 7.95 (s, 1H),7.47 (d, J=8.6 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 7.09-6.98 (m, 5H),6.33-6.06 (m, 1H), 4.56 (d, J=3.5 Hz, 1H), 3.86 (s, 3H), 3.75 (d, J=14.0Hz, 1H), 3.31-2.87 (m, 2H), 2.66-2.60 (m, 3H), 2.53 (s, 3H). Peak 2(Cpd. No. 112F, 49 mg), [α]_(D) −10.8° (c 0.24, CHCl₃), R_(t)=14.357min, ee>99%. MS (ESI) m/z 508.29 [M+1]⁺; UPLC: 96.14%. ¹H NMR (400 MHz,DMSO-d₆) δ 8.09 (s, 1H), 8.02 (s, 1H), 7.51 (d, J=7.8 Hz, 2H), 7.40 (d,J=7.1 Hz, 2H), 7.09-7.01 (m, 5H), 6.31-5.17 (m, 1H), 4.53 (d, J=7.0 Hz,1H), 3.90 (s, 3H), 3.79 (d, J=13.8, 1H), 3.15-2.95 (m, 2H), 2.53 (s,3H), 2.40 (s, 3H).

Example 1134-((4bS,5R,6S,7S,7aR)-6-((4,4-difluoropiperidin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 113F)

Synthesis ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4,4-difluoropiperidin-1-yl)methanone (3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 0.9 g, 1.8 mmol) in dichloromethane (10 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.03 g,5.41 mmol), 1-hydroxybenzotriazole (0.72 g, 5.41 mmol) andN,N-diisopropylethylamine (1.65 mL, 9.12 mmol) were added at 0° C. andstirred for 5 minutes before 4,4-difluoropiperidine hydrochloride (2,1.4 g, 9.12 mmol) was added at the same temperature and the mixture wasstirred for 16 h at RT. After completion, the reaction mass was dilutedwith dichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel column chromatography eluting with 0-4% methanol indichloromethane. The desired fractions were concentrated to affordrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4,4-difluoropiperidin-1-yl)methanone(3) as white solid. Yield: 0.67 g, 67%; MS (ESI) m/z 601.01[M+1]⁺.

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((4,4-difluoropiperidin-1-yl)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4)

To a solution ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4,4-difluoropiperidin-1-yl)methanone(3, 0.6 g, 1.00 mmol) in dry tetrahydrofuran (25 mL) at 0° C., bornaedimethyl sulphide complex (1.0 ml, 10.2 mmol) was added. The resultingmixture was stirred for 16 h at room temperature. After completion, thereaction mass was quenched with methanol at 0° C. and reflux at 80° C.for 6 h. After completion, the reaction mass was concentrated to givecrude product. The crude product was purified by silica gel columnchromatography using 1-5% methanol in dichloromethane as eluent. Thedesired fractions were concentrated torac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((4,4-difluoropiperidin-1-yl)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as white solid. Yield: 0.560 g, 95.7%; MS (ESI) m/z 587.17[M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-6-((4,4-difluoropiperidin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 113F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((4,4-difluoropiperidin-1-yl)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 0.50 g, 0.85 mmol) in N,N-dimethylformamide (10 mL), zinc cyanide(0.59 g, 5.12 mmol) and zinc dust (0.006 g, 0.10 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.009 g, 0.0025 mmol) andtris(dibenzylideneacetone)dipalladium (0.023 g, 0.025 mmol) were addedto the reaction, degassed for additional 5 min and heated the mixture at140° C. for 4 h. After completion, the reaction mass was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude product was purified by silica gelcolumn chromatography using 2-4% methanol in dichloromethane as eluent.The desired fractions were concentrated to affordrac-4-((4bS,5R,6S,7S,7aR)-6-((4,4-difluoropiperidin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.325 g, 71% (racemic mixture). The enantiomerswere separated by chiral preparative HPLC [chiralpak IC (4.6×250)mm, 5μ]in isocratic n-hexane/isopropanol 80/20 v/v. Peak-1 (79 mg), [α]_(D)+10.0° (c 0.27, CHCl₃), R_(t)=10.477 min, ee=99.90%; ¹H NMR (400 MHz,DMSO-d₆) δ 8.04 (s, 1H), 7.97 (s, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.39 (d,J=8.4 Hz, 2H), 7.09-6.98 (m, 5H), 5.73 (s, 1H), 5.08 (d, J=5.6 Hz, 1H),4.51 (s, 1H), 3.88 (s, 3H), 3.80 (d, J=14.0 Hz, 1H), 3.32 (s, 1H),2.70-2.49 (m, 5H), 2.15 (d, J=9.6 Hz, 1H), 1.97 (bs, 4H); MS (ESI) m/z458.3[M+1]⁺; Peak-2 (Cpd. No. 113F, 74 mg), [α]_(D) −4.4° (c 0.27,CHCl₃), R_(t)=13.904 min, ee=99.42%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.04(s, 1H), 7.97 (s, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H),7.09-6.98 (m, 5H), 5.73 (s, 1H), 5.08 (d, J=5.6 Hz, 1H), 4.51 (s, 1H),3.87 (s, 3H), 3.80 (d, J=14.0 Hz, 1H), 3.32 (s, 1H), 2.70-2.49 (m, 5H),2.15 (d, J=9.6 Hz, 1H), 1.97 (bs, 4H); MS (ESI) m/z 458.31[M+1]⁺.

Example 114Rac-((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(Cpd. No. 114F)

Synthesis ofrac-((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)((4bS,5R,6R7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(Cpd. No. 114F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 0.05 g, 0.10 mmol) in dichloromethane (5.0 mL),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.043 g, 0.32 mmol),hydroxybenzotriazole (0.04 g, 0.3 mmol) and N,N-diisopropylethylamine(0.09 mL, 0.5 mmol) were added at 0° C. and stirred the mixture for 5min. 8-Azabicyclo[3.2.1]octane (0.016 g, 0.15 mmol) was then added atsame temperature and the reaction was stirred at room temperature for 5h. After completion, reaction mass was diluted with dichloromethane (20mL) and washed with cold water. The organic layer was separated anddried over anhydrous sodium sulphate, filtered and concentrated underreduced pressure. The crude was purified by reverse phase HPLC to affordrac-((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(Cpd. No. 114F) as white solid. Yield: 23.0 mg, 43%. MS (ESI) m/z591.18[M+1]⁺; UPLC 99.6%; 1H NMR (400 MHz, DMSO-d₆, at High temperatureVT(373K) δ: 8.11 (s, 1H), 8.01 (s, 1H), 7.21 (d, J=8.6 Hz, 2H), 7.11 (d,J=8.1 Hz, 2H), 7.05-6.94 (m, 5H), 4.70 (d, J=4.8 Hz, 1H), 4.52 (d,J=13.2 Hz, 1H), 4.09-4.05 (m, 1H), 3.92 (s, 3H), 2.01-1.78 (m, 8H),1.60-1.55 (m, 4H).

Example 1154-((4bS,5R,6S,7S,7aR)-6-(((2,2-difluoroethyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 115F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.00 g, 2.01 mmol) in dichloromethane (20 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (1.15 g, 6.03 mmol),hydroxybenzotriazole (0.923 g, 6.03 mmol) and N,N-diisopropylethylamine(1.81 g, 14.08 mmol) were added and the mixture was stirred for 5 min.2,2-difluoroethan-1-amine (2, 0.814 g, 10.06 mmol) was then added at thesame temperature and the reaction was stirred for 16 h at roomtemperature. After completion, the reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by silica gel columnchromatography using 0-3% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3) as white solid. Yield: 1.00 g, 83%; MS (ESI) m/z 561.14[M+1]⁺.

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2,2-difluoroethyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(3, 1.0 g, 1.78 mmol) in dry tetrahydrofuran (60 ml) at 0° C., boranedimethyl sulphide complex (1.35 g, 70.85 mmol) was added drop wise overa period of 5 min. The reaction mass was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mass was quenched with methanol at 0° C. and heated to refluxfor 5 h. After completion, solvent was removed under reduced pressureand the residue was purified over a plug of silica gel eluting thecompound with 5% methanol in dichloromethane. The desired fractions wereconcentrated under reduced pressure to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2,2-difluoroethyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as white solid. Yield: 0.8 g, 82%; MS (ESI) m/z 547.20[M+1]⁺.

Synthesis of 4-((4bS,5R,6S,7S,7aR)-6-(((2,2-difluoroethyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 115F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2,2-difluoroethyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bcyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 0.6 g, 1.09 mmol) in N,N-dimethylformamide (10 mL), zinc cyanide(0.771 g, 6.59 mmol) and zinc dust (0.0085 g, 0.131 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.012 g, 0.021 mmol) andtris(dibenzylideneacetone)dipalladium (0.030 g, 0.032 mmol) were addedto the reaction, degassed for additional 5 min and mixture was heated at140° C. for 8 h. After completion, the reaction mass was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by silica gel columnchromatography using 2-3% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-4-((4bS,5R,6S,7S,7aR)-6-(((2,2-difluoroethyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.230 g, 42% (racemic); MS (ESI) m/z494.32[M+1]⁺. The enantiomers were separated by chiral HPLC [ChiralpakIA (4.6×250) mm, 5μ] in hexane/IPA=20/80 (v/v). Peak 1 (Cpd. No. 115F,113 mg), [α]_(D) +48.6° (c 0.283, CHCl₃), R_(t)=6.441 min, ee: 99.66%;MS (ESI) m/z 494.32[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (s, 1H),7.98 (s, 1H), 7.49 (d, J=8.36 Hz, 2H), 7.37 (d, J=8.36 Hz, 2H),7.08-7.05 (m, 3H), 7.00 (d, J=7.28 Hz, 2H), 6.10-5.70 (m, 1H), 5.70 (s,1H), 5.19 (d, J=5.16 Hz, 1H), 4.54 (s, 1H), 3.89 (s, 3H), 3.75 (d,J=14.24 Hz, 1H), 3.14 (d, J=12.56 Hz, 1H), 2.88 (t, J=15.42 Hz, 2H),2.69 (t, J=11.84 Hz, 1H), 2.54 (m, 1H). Peak-2 (117 mg), [α]_(D) −48.9°(c 0.35, CHCl₃), R_(t)=19.449 min, ee:99.67%; MS (ESI) m/z 494.32[M+1]⁺.1H NMR (400 MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.98 (s, 1H), 7.49 (d, J=8.36Hz, 2H), 7.37 (d, J=8.36 Hz, 2H), 7.08-7.05 (m, 3H), 7.00 (d, J=7.28 Hz,2H), 6.11-5.70 (m, 1H), 5.70 (s, 1H), 5.19 (d, J=5.16 Hz, 1H), 4.54 (s,1H), 3.89 (s, 3H), 3.75 (d, J=14.24 Hz, 1H), 3.14 (d, J=12.56 Hz, 1H),2.88 (t, J=15.42 Hz, 2H), 2.69 (t, J=11.84 Hz, 1H), 2.54 (m, 1H).

Example 116Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 116F)

Synthesis ofrac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)-N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide(Cpd. No. 116F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 0.07 g, 0.14 mmol) in dichloromethane (10 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.08 g,0.42 mmol), 1-hydroxybenzotriazole (0.064 g, 0.42 mmol) andN,N-diisopropylethylamine (0.2 mL, 0.98 mmol) were added at 0° C. andstirred the mixture for 5 min. 2,2-difluoroethan-1-amine (0.057 g, 0.70mmol) was then added at same temperature and the mixture was stirred for16 h at 40° C. After completion, reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by silica gel column chromatographyeluting with 3% methanol in dichloromethane. The desired fractions wereconcentrated to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 116F) as white solid. Yield: 0.05 g, 50.7%; MS (ESI) m/z561.19[M+1]⁺; Purity: 98.25%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (t, J=8.6Hz, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.23 (d, J=8.6 Hz, 2H), 7.06-7.03(m, 4H), 6.99-6.94 (m, 3H), 6.04-5.76 (m, 1H), 5.06 (d, J=4.72 Hz, 1H),4.61 (t, J=4.6 Hz, 1H), 4.36 (d, J=14.08 Hz, 1H), 3.94 (dd, J=14.16 &4.72 Hz, 1H), 3.87 (s, 3H) 3.48-3.36 (m, 2H).

Example 117Rac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-((2,2,2-trifluoroethyl)sulfonyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 117F)

Synthesis of 4-methylbenzenesulfonothioic S-acid, sodium salt (2)

A solution of sodium 4-methylbenzenesulfinate (1, 50.0 g, 280.6 mmol)and sulfur powder (8.96 g, 59.8 mmol) in pyridine (200 mL) was stirredat room temperature for 16 h. After completion, the solvent wasdistilled out under reduced pressure to get crude product, which waswashed with n-pentane and dried under vacuum to afford4-methylbenzenesulfonothioic S-acid, sodium salt (2) as brown solid.Yield: 55.0 g, 92.0%; MS (ESI) m/z 186.97[M−1]⁻.

Synthesis of S-(2,2,2-trifluoroethyl) 4-methylbenzenesulfonothioate (4)

To a solution of 4-methylbenzenesulfonothioic S-acid, sodium salt (2,10.0 g, 47.39 mmol) in N,N-dimethyl formamide (100 mL) at 0° C., K₂CO₃(6.54 g, 47.39 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate(3, 13.14 g, 56.8 mmol) were added. The reaction mass was stirred for 4h at room temperature. After completion, the reaction mixture wasdiluted with ice water and extracted with ethyl acetate. The organiclayer was separated and dried over anhydrous sodium sulphate, filteredand concentrated to give crude. The crude was purified by silica gelcolumn chromatography eluting with 5-10% in ethyl acetate in hexane. Thedesired fractions were concentrated to afford S-(2,2,2-trifluoroethyl)4-methylbenzenesulfonothioate (4) as colorless liquid. Yield: 2.6 g,20.0%; 1H NMR (400 MHz, DMSO-d₆) δ 7.81 (d, J=8.32, 2H), 7.37 (d,J=8.16, 2H), 3.77 (m, 2H), 2.46 (s, 3H);

Synthesis of rac-(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-6-((2,2,2-trifluoroethyl)thio)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(6)

To a solution ofrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(5, 1.0 g, 2.21 mmol) in dry tetrahydrofuran (20 mL), lithiumdiisopropyl amide (2.0 M solution in THF) (1.32 mL, 2.65 mmol) was addedat −78° C. The reaction mixture was stirred at −78° C. for 1.5 h. Asolution of S-(2,2,2-trifluoroethyl) 4-methylbenzenesulfonothioate (4,1.19 g, 4.42 mmol) in tetrahydrofuran was added at −78° C., then slowlyreaction mass was brought to room temperature. The reaction was stirredat room temperature for 16 h. After completion, cooled to 0° C.,quenched with saturated ammonium chloride solution, extracted with ethylacetate, dried over anhydrous sodium sulphate, filtered and concentratedto get crude product which was purified over a plug of silica geleluting the compound with 5% methanol in dichloromethane. The desiredfractions were concentrated under reduced pressure to affordrac-(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-6-((2,2,2-trifluoroethyl)thio)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(6) as white solid. Yield: 1.0 g, 80%; MS (ESI) m/z 566.35[M+1]⁺.

Synthesis ofrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-((2,2,2-trifluoroethyl)thio)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(7)

A solution ofrac-(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-6-((2,2,2-trifluoroethyl)thio)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(6, 1.0 g, 1.76 mmol) in acetonitrile (20 mL) was cooled at 0° C., tothis solution acetic acid (1.06 g, 17.65 mmol) and sodiumtriacetoxyborohydride (2.25 g, 10.59 mmol) were added. The resultingmixture was stirred for 12 h at room temperature. After completion, thereaction mixture was partitioned between saturated aqueous sodiumbicarbonate solution and ethyl acetate. The organic layer was separatedand dried over sodium sulphate, filtered and concentrated to give crude.The crude was purified by silica gel column chromatography eluting with5-6% in methanol in dichloromethane. The desired fractions wereconcentrated to affordrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-((2,2,2-trifluoroethyl)thio)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(7) as white solid. Yield: 0.81 g, 81.0%; MS (ESI) m/z 568.14[M+1]⁺.

Synthesis ofrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-((2,2,2-trifluoroethyl)sulfonyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 117F)

A solution ofrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-((2,2,2-trifluoroethyl)thio)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(7, 0.1 g, 0.175 mmol) in methanol (2 mL) was cooled at 0° C. then 30%hydrogen peroxide in water (0.1 mL, 0.87 mmol) and sodium tungstate(0.022 g, 0.0875 mmol) were added to the above solution. The resultingmixture was stirred for 12 h at room temperature. After completion, thesolvent was concentrated to give crude. The crude was purified bypreparative HPLC to affordrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-((2,2,2-trifluoroethyl)sulfonyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 117F) as white solid. Yield: 0.009 g, 9%; MS (ESI) m/z600.18[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (s, 1H), 8.02 (s, 1H),7.29 (d, J=8.6 Hz, 2H), 7.20 (d, J=9.4 Hz, 2H), 7.06 (m, 5H), 6.28 (d,J=5.8 Hz, 1H), 6.07 (s, 1H), 4.90 (d, J=11.6 Hz, 1H), 4.43 (m, 3H), 3.90(s, 3H).

Example 118Rac-4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(phenylsulfonyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 118F)

Synthesis ofrac-(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-6-(phenylthio)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(3)

To a solution ofrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(1, 1.0 g, 2.212 mmol) in tetrahydrofuran (20 ml) at −15° C., lithiumdiisopropylamide 1M in Tetrahydrofuran (4.42 ml, 4.424 mmol) was addedand stirred for 30 min. at same temperature followed by addition of1,2-diphenyldisulfane (2, 0.53 g, 2.433 mmol) andN,N-Dimethylpropyleneurea (1.1 ml). The reaction mixture was stirred atroom temperature for 6 hr. After completion, the mixture was quenchedwith water and extracted with ethyl acetate. The organic phase wasseparated, dried over sodium sulphate and concentrated under reducedpressure. The crude was purified by silica gel column chromatographyusing 45% ethyl acetate in hexanes as eluent. The desired fractions wereconcentrated to affordrac-(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-6-(phenylthio)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(3) as yellow solid. Yield: 0.9 g, 73%; MS (ESI) m/z 560.96[M+1]⁺.

Synthesis ofrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(phenylthio)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (4)

To a solution ofrac-(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-6-(phenylthio)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(3, 0.9 g, 1.60 mmol) in acetonitrile (36 ml) at 0° C., sodiumtriacetoxyborohydride (2.04 g, 9.64 mmol) was added portion wise over aperiod of 5 min followed by addition of acetic acid (0.96 g, 16.01mmol). The reaction mass was slowly brought to room temperature andstirred for additional 12 h. After completion, the reaction mixture waspartitioned between saturated aqueous sodium bicarbonate solution andethyl acetate. The organic layer was separated, washed with water, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude was purified by silica gel column chromatographyusing 65% ethyl acetate in hexanes as eluent. The desired fractions wereconcentrated to affordrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(phenylthio)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as off white solid. Yield: 0.6 g, 67%; MS (ESI) m/z 562.37[M−1]⁺.

Synthesis of rac-4-((4bS,5S, 6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(phenylthio)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(5)

To a solution ofrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(phenylthio)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 0.8 g, 1.42 mmol) in N,N-dimethylformamide (16 mL), zinc cyanide(0.251 g, 2.14 mmol) and zinc dust (0.01 g, 0.14 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.104 g, 0.14 mmol) andtris(dibenzylideneacetone)dipalladium (0.04 g, 0.042 mmol) were added tothe reaction, degassed for additional 5 min and mixture was heated at140° C. for 16 h. After completion, the reaction mass was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by silica gel columnchromatography using 2-3% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(phenythio)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(5) as yellow solid. Yield: 0.6 g, 83%; MS (ESI) m/z 509.5[M−1]⁺.

Synthesis of rac-4-((4bS,5S, 6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(phenylsulfonyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 118F)

To a solution ofrac-4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(phenylthio)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(5, 0.1 g, 0.196 mmol) in methanol (2.0 mL) at 0° C., 30% aqueoushydrogen peroxide (0.11 mL, 0.984 mmol) was added followed by theaddition of sodium tungstate (0.029 g, 0.098 mmol). The reaction masswas stirred for 36 h at room temperature. After completion, the solventwas removed under reduced pressure. The crude was diluted with water andextracted with 10% methanol in dichloromethane. The organic phase wasseparated, dried over anhydrous sodium sulphate and concentrated underreduced pressure to give crude. The crude was purified by preparativeHPLC to affordrac-4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(phenylsulfonyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 118F) as white solid. Yield: 0.025 g, 23.5%; MS (ESI) m/z541.3[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (s, 1H), 8.04 (s, 1H),7.60 (t, J=7.2 Hz, 1H), 7.52-7.47 (m, 4H), 7.44-7.38 (m, 4H), 6.97-6.91(m, 5H), 6.15-6.08 (m, 2H), 5.11 (dd, J=13.8 Hz, 4.0 Hz 1H), 4.69 (d,J=3.2 Hz, 1H), 4.33 (d, J=13.8 Hz, 1H), 3.87 (s, 3H).

Example 119Rac-4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(pyridin-2-ylsulfonyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 119F)

Synthesis of rac-2-thioxopyridin-1 (2H)-yl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 2.50 g, 5.03 mmol) and 2-mercaptopyridine 1-oxide (2, 0.958 g,7.54 mmol) in dichloromethane (60 mL) at 0° C.,N,N′-dicyclohexylcarbodiimide (1.5 g, 7.54 mmol) was added and thereaction was stirred for 16 h at room temperature in the dark. Aftercompletion, solvent was removed under reduced pressure and the residuewas diluted with dichloromethane and washed with cold water. The organiclayer was separated and dried over anhydrous sodium sulphate, filteredand concentrated to give crude. The crude was purified by trituratingwith n-pentane and diethyl ether to affordrac-2-thioxopyridin-1(2H)-yl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(3) as white solid. Yield: 1.80 g, 59%; MS (ESI) m/z 606.42[M+1]⁺.

Synthesis ofrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(pyridin-2-ylthio)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4)

To a solution of rac-2-thioxopyridin-1(2H)-yl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(3, 1.80 g, 2.97 mmol) in dry dichloromethane under nitrogen. Thereaction mixture was refluxed by using tungsten lamp (200 W) for 10 h.After completion, solvent was removed under reduced pressure and theresidue was purified over a plug of silica gel eluting the compound with3% methanol in dichloromethane. The desired fractions were concentratedunder reduced pressure to affordrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(pyridin-2-ylthio)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as white solid. Yield: 1.66 g, 54%; MS (ESI) m/z 563.36[M+1]⁺.

Synthesis of rac-4-((4bS,5S, 6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(pyridin-2-ylthio)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(5)

To a solution ofrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(pyridin-2-ylthio)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 0.4 g, 0.711 mmol) in N,N-dimethylformamide (10 mL), zinc cyanide(0.499 g, 4.27 mmol) and zinc dust (0.005 g, 0.085 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.008 g, 0.0142 mmol) andtris(dibenzylideneacetone)dipalladium (0.019 g, 0.0213 mmol) were addedto the reaction, degassed for additional 5 min. and mixture was heatedat 140° C. for 8 h. After completion, the reaction mass was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by silica gel columnchromatography using 2-3% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to afford Synthesis of rac-4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(pyridin-2-ylthio)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(5) as white solid. Yield: 0.2 g, 55%; MS (ESI) m/z 510.41[M+1]⁺.

Synthesis of rac-4-((4bS,5S, 6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(pyridin-2-ylsulfonyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 119F)

To a solution ofrac-4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(pyridin-2-ylthio)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(5, 0.20 g, 0.392 mmol) in methanol (75 mL) at 0° C., 30% aqueoushydrogen peroxide (0.066 g, 1.96 mmol) was added followed by theaddition of sodium tungstate (0.080 g, 0.275 mmol). The reaction masswas stirred for 18 h at room temperature. After completion, the solventwas removed under reduced pressure. The crude was diluted with water andextracted with dichloromethane. The organic phase was separated, driedover anhydrous sodium sulphate and concentrated under reduced pressureto give crude. The crude was purified by preparative HPLC to affordrac-4-((4b5,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(pyridin-2-ylsulfonyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 119F) as white solid Yield: 0.025 g, 11.7%; MS (ESI) m/z542.28[M+1]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.79 (d, J=4.12 Hz, 1H), 8.06(s, 1H), 7.99 (s, 1H), 7.79 (t, J=7.30 Hz, 1H), 7.63 (t, J=5.56 Hz, 1H),7.51 (d, J=8.0 Hz, 2H), 7.39-7.37 (m, 3H), 6.84 (t, J=7.1 Hz, 1H), 6.74(t, J=7.28 Hz, 2H), 6.58 (d, J=7.28 Hz, 2H), 6.18 (s, 1H), 6.06 (d,J=5.92 Hz, 1H), 5.24 (dd, J=15.64 Hz,4.92 Hz, 1H), 4.88 (t, J=9.8 Hz,1H), 4.56 (d, J=13.8 Hz, 1H), 3.86 (s, 3H).

Example 1204-((4bR,5R,7S,7aR)-4b-hydroxy-5-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 120F)

Synthesis ofrac-(4bR,7S,7aR,E)-7a-(4-bromophenyl)-4-methoxy-5-(methoxymethylene)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(3)

To a solution ofrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(1, 0.5 g, 1.105 mmol) in methanol (20 mL) at 0° C. was added dimethyl(1-diazo-2-oxopropyl)phosphonate (2, 0.248 mL, 1.658 mmol) followed byK₂CO₃ (0.305 g, 2.210 mmol). The reaction mixture was stirred at 0° C.for 30 min then the reaction mixture was stirred at room temperature for16 h. After completion of the reaction it was quenched by the additionof saturated sodium bicarbonate solution (30 mL). The precipitated solidwas filtered, washed with water, n-pentane and dried under vacuum toaffordrac-(4bR,7S,7aR,E)-7a-(4-bromophenyl)-4-methoxy-5-(methoxymethylene)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(3) as white solid. Yield: 0.4 g, 75%; MS (ESI) m/z 480.18[M+1]⁺;482.19[M+2]⁺; LCMS shows desired mass in two peaks (71%+20%).

Synthesis ofrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-5-carbaldehyde(4)

To a solution ofrac-(4bR,7S,7aR,E)-7a-(4-bromophenyl)-4-methoxy-5-(methoxymethylene)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(3, 0.4 g, 0.832 mmol) in THF (6 mL) at 0° C. was added 6N hydrochloricacid (1 mL). The reaction mixture was stirred for 3 h at roomtemperature. After completion, the reaction mass was cooled andneutralized by the addition of saturated sodium bicarbonate up to pH ˜7and extracted with ethyl acetate. The organic layer was separated anddried over anhydrous sodium sulphate, filtered and concentrated, thecrude product obtained was triturated in n-pentane and the solid wasfiltered off to giverac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-5-carbaldehyde(4) as pale yellow solid. Yield: 0.3 g, 79%; MS (ESI) m/z 464.12[M−1]⁻;466.13[M−2]⁻. LCMS shows desired mass in two peaks (57%+23%).

Synthesis ofrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-5-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(5)

To a solution ofrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-5-carbaldehyde(4, 0.3 g, 0.643 mmol) in methanol (12 mL) at 0° C., sodium borohydride(0.06 g, 1.608 mmol) was added in one portion. The reaction mixture wasstirred for 2 h at room temperature. After completion, the reactionmixture was cooled and quenched with ice water. The precipitated solidwas filtered off, washed with water, n-pentane and mixture of 10% etherin pentane and dried under vacuum to affordrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-5-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(5) as white solid. Yield: 0.2 g, 67%; MS (ESI) m/z 468.17[M+1]⁺;470.15[M+2]⁺. LCMS shows desired mass in two peaks (82%+7%).

Synthesis of 4-((4bR,5R,7S,7aR)-4b-hydroxy-5-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 120F)

To a solution ofrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-5-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(5, 0.30 g, 0.64 mmol) in N,N-dimethylformamide (6.0 mL), zinc cyanide(0.112 g, 0.96 mmol) and zinc dust (0.0041 g, 0.064 mmol) were added atroom temperature and mixture was degassed with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.046 g, 0.064 mmol), andtris(dibenzylideneacetone)dipalladium (0.017 g, 0.0192 mmol) were addedto the above reaction mixture and the degassing was continued foranother 5 minute. The reaction mixture was heated at 140° C. for 3 h.After completion, the reaction mass was diluted with ethyl acetate andwashed with cold water. The organic layer was separated and dried oversodium sulphate, filtered and concentrated to give crude. The crude waspurified by silica gel column chromatography eluting with 2-3% methanolin dichloromethane. The desired fractions were concentrated to affordrac-4-((4bR,5R,7S,7aR)-4b-hydroxy-5-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.2 g, 75%. (Racemic mixture); MS (ESI) m/z415.42[M+1]+; The enantiomers were separated by chiral preparative HPLC[chiralpak IC (4.6×250) mm, 5μ] with isocratic 0.1% triethylamine inn-hexane/isopropanol 80/20 v/v. Peak 1 (Cpd. No. 120F, 50 mg), [α]_(D)−74.5° (c 0.22, CDCl₃), R_(t)=28.294 min, ee=99.64%; ¹H NMR (400 MHz,DMSO-d₆) δ: 8.16 (s, 1H), 8.08 (s, 1H), 7.58 (d, J=8.28 Hz, 2H), 7.41(d, J=8.28 Hz, 2H), 7.11 (m, 3H), 6.97 (d, J=7.28 Hz, 2H), 5.49 (s, 1H),4.60 (t, J=5.16 Hz, 1H), 4.09 (t, J=5.8 Hz, 1H), 3.96 (s, 3H), 3.93 (t,J=6.68 Hz, 1H), 3.54 (dd, J=5.6 Hz, J=5.48 Hz, 1H), 2.71 (d, J=Hz 1H),2.42 (d, J=7.12 Hz, 1H), 2.25 (t, J=6.12 Hz, 1H); Peak-2 (45 mg),[α]_(D) +75.0° (c 0.20, CDCl₃), R_(t)=38.405 min, ee>99% ¹H NMR (400MHz, DMSO-d₆) δ: 8.16 (s, 1H), 8.08 (s, 1H), 7.58 (d, J=8.36 Hz, 2H),7.41 (d, J=8.24 Hz, 2H), 7.11 (m, 3H), 6.97 (d, J=7.2 Hz, 2H), 5.49 (s,1H), 4.60 (t, J=4.12 Hz, 1H), 4.09 (t, J=5.72 Hz, 1H), 3.96 (s, 3H),3.93 (t, J=6.96 Hz, 1H), 3.54 (dd, J=5.88 Hz, J=5.72 Hz, 1H), 2.75 (t,J=8.08 Hz 1H), 2.45 (d, J=9.4 Hz, 1H), 2.25 (t, J=6.68 Hz, 1H).

Example 121Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(3,3-difluoroazetidin-1-yl)methanone(Cpd. No. 121F)

Synthesis ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(3,3-difluoroazetidin-1-yl)methanone(Cpd. No. 121F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.50 g, 3.01 mmol) in dichloromethane (20 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (1.72 g, 9.05 mmol),hydroxybenzotriazole (1.40 g, 9.045 mmol) and N,N-diisopropylethylamine(3.20 g, 18.1 mmol) were added and the mixture was stirred for 5 minute.3,3-difluoroazetidine hydrochloride (1.16 g, 9.05 mmol) was then addedat the same temperature and the reaction was stirred for 16 h at roomtemperature. After completion, the reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel column chromatography using 0-5% methanol in dichloromethaneas eluent. The desired fractions were concentrated to affordrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(3,3-difluoroazetidin-1-yl)methanone(Cpd. No. 121F) as white solid. Yield: 1.20 g, 70%; MS (ESI) m/z573.18[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (s, 1H), 7.99 (s, 1H),7.21 (d, J=8.8 Hz, 2H), 7.08-7.03 (m, 4H), 6.99 (m, 3H), 5.67 (s, 1H),5.34 (d, J=5.2 Hz, 1H), 5.15 (d, J=11.2 Hz, 1H), 4.75 (m, 2H), 4.36 (d,J=13.6 Hz, 1H), 4.22 (bs, 3H), 4.02 (dd, J=13.6, 5.2 Hz, 1H), 3.88 (s,3H).

Example 1224-((4bS,5R,6S,7S,7aR)-6-((3,3-difluoroazetidin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No. 122F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((3,3-difluoroazetidin-1-yl)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(3,3-difluoroazetidin-1-yl)methanone(1, 1.20 g, 2.09 mmol) in dry tetrahydrofuran (20 mL) at 0° C., bornaedimethyl sulphide complex (1.90 ml, 20.9 mmol) was added at the sametemperature and the reaction was stirred for 16 h at room temperature.After completion, the reaction mass was diluted with methanol at 0° C.and reflex at 80° C. for 6 h. After completion, the reaction mixture wasconcentrated to obtain crude product. The crude product was purified bysilica gel column chromatography using 0-5% methanol in dichloromethaneas eluent. The desired fractions were concentrated under reducedpressure to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((3,3-difluoroazetidin-1-yl)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 0.60 g, 51%; MS (ESI) m/z 559.24[M+1]⁺.

Synthesis of 4-((4bS,5R,6S,7S,7aR)-6-((3,3-difluoroazetidin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 122F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((3,3-difluoroazetidin-1-yl)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.60 g, 1.04 mmol) in N,N-dimethylformamide (10 mL), zinc cyanide(0.60 g, 5.23 mmol) and zinc dust (0.0079 g, 0.124 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15minute. 1,1′-Bis(diphenylphosphino)ferrocene (0.012 g, 0.0208 mmol) andtris(dibenzylideneacetone)dipalladium (0.028 g, 0.0312 mmol) were addedto the reaction, degassed for additional 5 minute and heated the mixtureat 140° C. for 1 h. After completion, the reaction mass was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel column chromatography using 2-3% methanol in dichloromethaneas eluent. The desired fractions were concentrated to affordrac-4-((4bS,5R,6S,7S,7aR)-6-((3,3-difluoroazetidin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.330 g, 61% (racemic), MS (ESI) m/z 506.27[M+1]⁺. The enantiomers were separated by chiral preparative HPLC[chiralpak IC (4.6×250) mm, 5μ] in isocratic 0.1% triethylamine inhexane/isopropanol 80/20 v/v. Peak 1 (80 mg), [α]_(D)−8.1° (c 0.43,CHCl₃), R_(t)=10.350 min, ee=99.54%, ¹H NMR (400 MHz, DMSO-d₆) δ 8.04(s, 1H), 7.97 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz 2H),7.10 (m, 2H), 7.02 (m, 3H), 5.74 (s, 1H), 5.23 (d, J=5.2 Hz, 1H), 4.48(t, J=4.8 Hz, 1H), 3.88 (s, 1H), 3.81 (d, J=14 Hz, 1H), 3.67 (m, 4H),3.05 (m, 1H), 2.80 (m, 1H), 2.50 (bs, 1H); Peak 2 (Cpd. No. 122F, 85mg), [α]_(D) +9.0° (c 0.43, CHCl₃), R_(t)=14.833 min, ee=99.18%, ¹H NMR(400 MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.97 (s, 1H), 7.49 (d, J=8.4 Hz, 2H),7.37 (d, J=8.4 Hz, 2H), 7.10 (m, 2H), 7.02 (m, 3H), 5.74 (s, 1H), 5.23(d, J=5.2 Hz, 1H), 4.48 (t, J=4.8 Hz, 1H), 3.88 (s, 1H), 3.81 (d, J=14Hz, 1H), 3.67 (m, 4H), 3.05 (m, 1H), 2.80 (m, 1H), 2.50 (bs, 1H).

Example 123Rac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(Cpd. No. 123F)

Synthesis of ((E)-2-phenylethene-1-sulfonyl chloride (2)

To a solution of styrene (1, 55.00 g, 528.0 mmol) inN,N-dimethylformamide (50 mL) at 0° C., sulfuryl chloride (142.0 g,1056.1 mmol) was added and the reaction mixture was stirred at roomtemperature for 2 h. After completion, the mixture was quenched with icecold water (500 mL) and the mixture was extracted with ethyl acetate(1000 mL). The organic layer was washed with water and brine, separatedand dried over anhydrous sodium sulphate, filtered then concentratedunder reduced pressure to afford (E)-2-phenylethene-1-sulfonyl chloride(2) as white solid. Yield: 90.0 g, crude.

Synthesis of (E)-N-benzyl-N-methyl-2-phenylethene-1-sulfonamide (4)

To a solution of (E)-2-phenylethene-1-sulfonyl chloride (2, 35.00 g,173.26 mmol) in dichloromethane (100 mL), triethylamine (25.0 mL, 173.26mmol) and N-methyl-1-phenylmethanamine (3, 20 mL, 156.0 mmol) wereadded. The reaction mixture was stirred at room temperature for 16 h.After completion, solvent was removed under reduced pressure. Themixture was quenched with ice cold aqueous solution of sodiumbicarbonate (300 mL) and extracted with ethyl acetate (1000 mL). Theorganic layer was washed with water and brine, dried over anhydroussodium sulphate, filtered and concentrated under reduced pressure togive crude. The crude was purified by silica gel (100-200 mesh) columnchromatography using 50% ethyl acetate in hexanes as eluents. Thedesired fractions were concentrated under reduced pressure to afford(E)-N-benzyl-N-methyl-2-phenylethene-1-sulfonamide (4) as white solid.Yield: 9.0 g, 18%; MS (ESI) m/z 288.23[M+1]⁺.

Synthesis ofN-benzyl-5a-(4-bromophenyl)-3-chloro-7a-hydroxy-N-methyl-8-oxo-6-phenyl-5a,6, 7a, 8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-sulfonamide (6 & 6a)

A solution of2-(4-bromophenyl)-7-chloro-3-hydroxy-4H-pyrano[3,2-b]pyridin-4-one (5,3.0 g, 8.54 mmol) and (E)-N-benzyl-N-methyl-2-phenylethene-1-sulfonamide(4, 7.0 g, 25.64 mmol) in dichloromethane (100 mL), acetonitrile (50 mL)and methanol (50 mL) was placed in a UV reactor flask. The reactionmixture was irradiated under 400 watts UV light for 96 h. Aftercompletion, solvent was removed under reduced pressure and the residuewas purified over a plug of silica gel (100-200 mesh) eluting thecompound with ethyl acetate. The desired fractions were concentratedunder reduced pressure to affordN-benzyl-5a-(4-bromophenyl)-3-chloro-7a-hydroxy-N-methyl-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-sulfonamide(6 & 6a) as brown sticky solid. Yield: 1.3 g, crude.

Synthesis ofrac-(5aR,6S,8aR)-N-benzyl-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-N-methyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(7)

The crude compoundN-benzyl-5a-(4-bromophenyl)-3-chloro-7a-hydroxy-N-methyl-8-oxo-6-phenyl-5a,6,7a,8-tetrahydro-7H-cyclobuta[5,6]pyrano[3,2-b]pyridine-7-sulfonamide(6 & 6a, 1.30 g) was suspended in methanol (15 mL) and treated with 25%sodium methoxide solution in methanol (15 mL). The reaction was heatedat 90° C. for 3 h. After completion, the solvent was removed underreduced pressure. The crude was diluted with ammonium chloride solutionand extracted with ethyl acetate. The organic phase was separated, driedover anhydrous sodium sulphate and concentrated under reduced pressureto affordrac-(5aR,6S,8aR)-N-benzyl-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-N-methyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(7) as brown sticky solid. Yield: 1.3 g, crude.

Synthesis ofrac-(5aR,6S,7R,8S,8aS)-N-benzyl-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(Cpd. No. 123F)

To a solution of sodium triacetoxyborohydride (1.20 g, 5.64 mmol),rac-(5aR,6S,8aR)-N-benzyl-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-N-methyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(7, 0.6 g, 0.94 mmol) in acetonitrile (10 mL), acetic acid (0.56 g, 9.40mmol) was added. The resulting mixture was stirred for 16 h at roomtemperature. After completion, the reaction mixture was partitionedbetween saturated aqueous sodium bicarbonate solution and ethyl acetate.The organic layer was separated, dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to get the crude. Thecrude product was purified by Combi-flash (12 g RediSep column) using50% ethyl acetate in hexanes as eluents. The desired fractions wereconcentrated under reduced pressure to affordrac-(5aR,6S,7R,8S,8aS)-N-benzyl-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(Cpd. No. 123F) as brown solid. Yield: 0.23 g, 39.0%; MS (ESI) m/z641.09[M+1]⁺; UPLC 98.0%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (d, J=1.9 Hz,1H), 7.67 (d, J=1.9 Hz. 1H), 7.32-7.29 (m, 3H), 7.26-7.23 (m, 4H),7.20-7.15 (m, 4H), 7.12-7.02 (m, 3H), 6.36 (s, 1H), 6.02 (s, 1H), 4.99(dd, J=4.7 Hz, 13.6 Hz, 1H), 4.70 (d, J=3.4 Hz, 1H), 4.59 (d, J=13.7 Hz,1H), 4.00 (d, J=15.8 Hz, 1H), 3.75 (m, 1H), 2.37 (s, 3H).

Example 124Rac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(Cpd. No. 124F)

Synthesis ofrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(Cpd. No. 124F)

To a solution ofrac-(5aR,6S,7R,8S,8aS)-N-benzyl-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(1, 0.190 g, 0.290 mmol) in dichloromethane (2 mL), trifluoroacetic acid(2.0 mL) and triflic acid (2.0 mL) were added and the reaction wasstirred for 3 h at room temperature. After completion, the reaction wasdiluted with dichloromethane and washed with cold sodium bicarbonateaqueous solution. The organic layer was separated and dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure to affordrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(Cpd. No. 124F) as brown solid. Yield: 0.18 g, 92.0%; MS (ESI) m/z 550.9[M+1]+; UPLC 99.3%; 1H NMR (400 MHz, DMSO-d₆) δ 8.20 (d, J=1.8 Hz, 1H),7.66 (d, J=1.8 Hz. 1H), 7.21 (d, J=8.6 Hz, 2H), 7.14 (d, J=8.6 Hz, 4H),7.08-6.95 (m, 3H), 6.28 (bs. 1H), 6.27-6.25 (m, 1H), 5.84 (bs, 1H), 4.79(dd, J=4.3 Hz, 13.5 Hz, 1H), 4.69 (m, 1H), 4.55 (d, J=13.6 Hz, 1H), 2.43(d, J=4.8 Hz, 3H).

Example 125Rac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(Cpd No. 125F)

Synthesis ofrac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(Cpd. No. 125F)

To a solution ofrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(1, 0.065 g, 0.11 mmol) in N,N-dimethylformamide (3.0 mL), zinc cyanide(0.028 g, 0.23 mmol) and zinc dust (0.031 g, 0.472 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (1 mg, 0.0024 mmol) andtris(dibenzylideneacetone)dipalladium (2 mg, 0.0024 mmol) were added tothe reaction, degassed for additional 5 min and heated the mixture at125° C. for 6 h. After completion, the reaction mass was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated. The crude was purified by Combi-flash (12 g RediSepcolumn) using 3% methanol: dichloromethane as eluent, further itpurified by reverse prep HPLC. The desired fractions were lypholized toaffordrac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide(Cpd. No. 125F) as off white solid. Yield: 4 mg, 4% (racemic mixture).MS (ESI) m/z 498.17 [M+1]+; UPLC 98.3%; 1H NMR (400 MHz, DMSO-d₆) δ 8.21(s, 1H), 7.70 (s, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H),7.16 (d, J=7.4 Hz, 2H), 7.01 (t, J=7.2 Hz, 3H), 6.41 (s, 1H), 6.30 (d,J=4.3 Hz, 1H), 5.90 (d, J=5.9 Hz, 1H), 4.90 (dd, J=4.0 Hz, 13.4 Hz, 1H),4.69 (m, 1H), 4.60 (d, J=13.8, 1H), 2.50 (s, 3H).

Example 1264-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(morpholinosulfonyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 126F)

Synthesis of (E)-4-(styrylsulfonyl)morpholine (2)

To a solution of morpholine, (0.65 mL, 355.3 mmol) in dichloromethane(700 mL) at 0° C., triethylamine (109.4 mL, 888.2 mmol) and solution of(E)-2-phenylethene-1-sulfonyl chloride (1, 60.0 mL, 296.0 mmol) indichloromethane was added drop wise over a period of 15 min. Thereaction mass was slowly brought to room temperature and stirred foradditional 16 h. After completion, the reaction mass was diluted withdichloromethane (500 mL) and water (250 mL). The organic layer wasseparated, washed with water, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The crude was purifiedby silica gel column chromatography using 20% ethyl acetate in hexanesas eluent. The desired fractions were concentrated to afford(E)-4-(styrylsulfonyl)morpholine (2) as white solid. Yield: 38.0 g,50.6%; MS (ESI) m/z 254.19[M−1]⁺.

Synthesis ofrac-(3S,4S,5R)-2-(4-bromophenyl)-5-hydroxy-6-methoxy-4-(morpholinosulfonyl)-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridin-10-one(4)

A solution of2-(4-bromophenyl)-3-hydroxy-5-methoxy-4H-pyrano[2,3-c]pyridin-4-one (3,5.0 g, 14.36 mmol) and (E)-4-(styrylsulfonyl)morpholine (2, 36.86 g,113.4 mmol) in dichloromethane (150 mL), acetonitrile (150 mL) andmethanol (150 mL) was placed in a UV reactor flask. The reaction mixturewas irradiated under 400 watts UV light for 72 h. After completion,solvent was removed under reduced pressure and the residue was purifiedover a plug of silica gel eluting the compound with ethyl acetate. Thedesired fractions were concentrated under reduced pressure to affordrac-(3S,4S,5R)-2-(4-bromophenyl)-5-hydroxy-6-methoxy-4-(morpholinosulfonyl)-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridin-10-one(4) as yellow brown solid. Yield: 4.05 g, crude. MS (ESI) m/z601.42[M−1]⁺.

Synthesis ofrac-(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-6-(morpholinosulfonyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(5)

A solution ofrac-(3S,4S,5R)-2-(4-bromophenyl)-5-hydroxy-6-methoxy-4-(morpholinosulfonyl)-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridin-10-one(4, 2.0 g, 3.32 mmol) was suspended in methanol (40 mL) and treated with25% sodium methoxide in methanol (7.1 mL, 33.25). The reaction washeated at 80° C. for 4 h. After completion, the solvent was removedunder reduced pressure. The crude was diluted with ammonium chloridesolution and extracted with ethyl acetate. The organic phase wasseparated, dried over anhydrous sodium sulphate and concentrated underreduced pressure to affordrac-(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-6-(morpholinosulfonyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(5) as brown solid. Yield: 1.8 g, crude; MS (ESI) m/z 601.31[M+1]⁺.

Synthesis ofrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(morpholinosulfonyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(6)

A solution ofrac-(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-6-(morpholinosulfonyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(5, 2.0 g, 3.32 mmol) in acetonitrile (40 mL) was cooled at 0° C.,acetic acid (1.99 g, 33.25 mmol) and sodium triacetoxyborohydride (7.21g, 33.25 mmol) were added. The resulting mixture was stirred for 12 h atroom temperature. After completion, the reaction mixture was partitionedbetween saturated aqueous sodium bicarbonate solution and ethyl acetate.The organic layer was separated and dried over sodium sulphate, filteredand concentrated to give crude. The crude was purified by silica gelcolumn chromatography eluting with 2-3% in methanol in dichloromethane.The desired fractions were concentrated to affordrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(morpholinosulfonyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(6) as white solid. Yield: 0.4 g, 20%; MS (ESI) m/z 601.41[M−1]⁻.

Synthesis of 4-((4bR,5R,7S,7aR)-4b-hydroxy-5-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 126F)

To a solution ofrac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(morpholinosulfonyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(6, 0.4 g, 0.662 mmol) in N,N-dimethylformamide (8.0 mL), zinc cyanide(0.468 g, 3.97 mmol) and zinc (0.0052 g, 0.079 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.0096 g, 0.0132 mmol) andtris(dibenzylideneacetone)dipalladium (0.0018 g, 0.00199 mmol) wereadded to the reaction and degassing was continued for another 5 min. Thereaction mixture was heated at 140° C. for 3 h. After completion, thereaction mass was diluted with ethyl acetate and washed with cold water.The organic layer was separated and dried over sodium sulphate, filteredand concentrated to give crude. The crude was purified by silica gelcolumn chromatography eluting with 2-3% methanol in dichloromethane. Thedesired fractions were concentrated to afford rac-4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(morpholinosulfonyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.28 g, 77%. (Racemic mixture); MS (ESI) m/z550.41[M+1]+; The enantiomers were separated by chiral preparative HPLC[chiralpak IA (4.6×250) mm, 5μ] with isocratic hexane/Ethanol 25/75 v/vto afford Peak 1 (Cpd. No. 126F, 50 mg), [α]_(D) +49.5° (c 0.20, DMSO),R_(t)=8.916 min, ee>99% ¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (s, 1H), 7.99(s, 1H), 7.51 (m, 4H), 7.14 (d, J=7.28 Hz, 2H), 7.06 (m, 3H), 6.02 (bs,2H), 4.96 (dd, J=3.88 Hz, J=3.96 Hz, 1H), 4.72 (d, J=3.72 Hz, 1H), 4.49(d, J=13.72 Hz, 1H), 3.88 (s, 3H), 3.41 (m, 4H), 2.96 (d, J=12.88 Hz,2H), 2.86 (d, J=8.4 Hz, 2H); Peak-2 (50 mg), [α]_(D) −47.5° (c 0.29,DMSO), R_(t)=22.074 min, ee>97% ¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (s,1H), 7.99 (s, 1H), 7.50 (m, 4H), 7.14 (d, J=7.2 Hz, 2H), 7.05 (m, 3H),6.02 (bs, 2H), 4.95 (dd, J=9.64 Hz, 1H), 4.72 (d, J=4.04 Hz, 1H), 4.49(d, J=13.68 Hz, 1H), 3.88 (s, 3H), 3.40 (m, 4H), 2.97 (d, J=9.92 Hz,2H), 2.86 (d, J=5.76 Hz, 2H).

Example 127Rac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 127F)

Synthesis of rac-2-thioxopyridin-1(2H)-yl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2)

To a mixture ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (1, 350 mg, 0.70 mmol) and 1-hydroxypyridine-2(1H)-thione (1a, 443mg, 3.48 mmol) in dichloromethane (10 mL) was addedN,N′-Dicyclohexylcarbodiimide (0.16 mL, 1.04 mmol) and stirredvigorously for 4 h. LCMS analysis showed complete consumption of theacid starting material and desired product was observed. The reactionmixture was filtered to remove the urea and concentrated to provide thecrude desired product, rac-2-thioxopyridin-1(2H)-yl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2). MS (ESI) m/z 611.2[M+1]⁺. The crude product was used directly inthe following step.

Synthesis ofrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a, 6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd. No.127F)

The crude material, rac-2-thioxopyridin-1(2H)-yl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2) in benzene (50 mL) was treated with tributylstannane (0.55 mL, 2.03mmol) and azobisisobutyronitrile (22 mg, 0.14 mmol) and heated 80° C.and stirred vigorously in the absence of light for 3 h. After which timethe reaction mixture was concentrated in-vacuo, re-dissolved inN,N-dimethylformamide and filtered through a 5 micron membrane. Thecrude material was purified by reverse phase HPLC to affordrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 127F) as a white solid. Yield: 0.031 g, 10%; MS (ESI) m/z460.1[M+1]⁺; ¹H NMR (300 MHz, Chloroform-d) δ 8.23 (s, 1H), 7.69 (s,1H), 7.30-7.26 (m, 2H), 7.21-7.13 (m, 3H), 7.05-7.01 (m, 4H), 5.01 (dd,J=5.7, 3.4 Hz, 1H), 4.20 (dd, J=11.6, 6.7 Hz, 1H), 2.89-2.78 (m, 1H).

Example 128Rac-4-((5aR,6S,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 128F)

Synthesis ofrac-4-((5aR,6S,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 128F)

To a solution ofrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(1, 1a mg, 0.020 mmol) in N,N-dimethylformamide (3 mL), zinc cyanide (17mg, 0.14 mmol) and zinc (1 mg, 0.015 mmol) were added and degassed themixture with nitrogen for 15 min. 1,1′-Bis(diphenylphosphino)ferrocene(1 mg, 0.0015 mmol), tris(dibenzylideneacetone)dipalladium (1 mg, 0.0011mmol) were added to the above reaction and degassing was continued foranother 5 min followed by heating the reaction mixture at 140° C. for 1h. After completion, the reaction was cooled to room temperature andfiltered. The filtrate was purified by reverse phase prep HPLC toprovide the desired product then purified by preparatory thin layerchromatography (dichloromethane/MeOH) and prep HPLC to affordrac-4-((5aR,6S,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 128F) as a white powder. Yield: 0.0015 g, 15.6%; MS (ESI) m/z405.1[M+1]⁺; ¹H NMR (300 MHz, Chloroform-d) δ 8.21 (s, 1H), 7.62 (s,1H), 7.47-7.38 (m, 2H), 7.36-7.26 (m, 2H), 7.17-7.12 (m, 3H), 7.01-6.97(m, 2H), 5.00 (dd, J=5.7, 2.7 Hz, 1H), 4.23 (dd, J=12.4, 6.7 Hz, 1H),2.87 (td, J=13.2, 5.6 Hz, 1H), 2.38-2.30 (m, 1H).

Example 129Rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(Cpd. No. 129F)

Synthesis ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a, 6,7, 8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one (Cpd. No.129F)

A mixture of rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(1,500 mg, 0.97 mmol) and lithium chloride (0.21 mL, 1.94 mmol) in dimethylsulfoxide (5 mL) was heated to 140° C. and stirred for 4 h. LCMSanalysis of the reaction mixture showed complete conversion to thedesired product. The reaction mixture was directly purified by prep HPLCto affordrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(Cpd. No. 129F) as a white powder. Yield: 0.350 g, 79%; MS (ESI) m/z458.1[M+1]⁺; ¹H NMR (300 MHz, Chloroform-d) δ 8.30 (d, J=1.9 Hz, 1H),7.52 (d, J=2.0 Hz, 1H), 7.35-7.30 (m, 2H), 7.21-7.16 (m, 3H), 6.99-6.93(m, 4H), 3.91-3.76 (m, 2H), 3.10 (dd, J=10.9, 1.9 Hz, 2H).

Example 130Rac-(5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 130F)

Synthesis ofrac-(5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd.No. 130F)

To a solution ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(1, 43 mg, 0.09 mmol) in methanol (1 mL) and THF (1 mL) was added sodiumborohydride (11 mg, 0.28 mmol) at 0° C. After stirring for 1 h, thereaction mixture was quenched by addition of saturated aqueous NH₄Cl (50mL). The mixture was extracted with EtOAc (3×50 mL), washed with brine(50 mL), dried over Na₂SO₄. The crude material was purified by prep HPLCto affordrac-(5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 130F) as a white solid. Yield: 0.023 g, 53%; MS (ESI) m/z476.35[M+1]⁺; ¹H NMR (300 MHz, Chloroform-d) δ 8.22 (s, 1H), 7.60 (d,J=1.8 Hz, 1H), 7.38-7.25 (m, 2H), 7.19-7.05 (m, 5H), 6.96 (dd, J=6.7,2.9 Hz, 2H), 4.91-4.79 (m, 1H), 3.37 (dd, J=14.9, 6.5 Hz, 1H), 2.70 (dt,J=13.9, 7.1 Hz, 1H), 2.48 (td, J=14.2, 8.6 Hz, 1H).

Example 131Rac-4-((5aR,6S,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 131F)

Synthesis ofrac-4-((5aR,6S,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 131F)

A mixture ofrac-(5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(1, 19.4 mg, 0.04000 mmol), zinc cyanide (29.79 mg, 0.25000 mmol) andzinc (0.41 mg, 0.01000 mmol) in N,N-dimethylformamide (3 mL) wasdegassed with nitrogen for 15 min. Bis(diphenylphosphino)ferrocene (0.47mg, 0 mmol), tris(dibenzylideneacetone)-dipalladium (1.16 mg, 0 mmol)were added and degassed for another 5 min followed by heating thereaction mixture at 140° C. for 1 h. After completion, the reaction wascooled to room temperature and filtered. The filtrate was purified byreverse phase prep HPLC to affordrac-4-((5aR,6S,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 131F) as a white solid. Yield: 0.006 g, 35%; MS (ESI) m/z405.0[M+1]⁺; ¹H NMR (300 MHz, Chloroform-d) δ 8.23 (s, 1H), 7.52 (d,J=1.6 Hz, 1H), 7.41 (d, J=41.6 Hz, 4H), 7.11 (t, J=3.2 Hz, 3H),6.96-6.88 (m, 2H), 4.86 (t, J=7.7 Hz, 1H), 3.41 (dd, J=14.7, 6.7 Hz,1H), 2.76-2.63 (m, 1H), 1.25 (s, 1H).

Example 132Rac-N′-((5aR,6S,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylidene)-4-methylbenzenesulfonohydrazide(Cpd. No. 132F)

Synthesis ofrac-N′-((5aR,6S,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6, 7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylidene)-4-methylbenzenesulfonohydrazide(Cpd. No. 132F)

To a solution ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(1, 194. mg, 0.42000 mmol) in methanol (3 mL) was added4-methylbenzenesulfonohydrazide (2, 87.01 mg, 0.47000 mmol) and thereaction was allowed to stir for 6 h at 70° C. Upon cooling the productprecipitated. The product was filtered and washed with diethyl ether toaffordrac-N′-((5aR,6S,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylidene)-4-methylbenzenesulfonohydrazide(Cpd. No. 132F) as a white solid. Yield: 0.090 g, 34%; MS (ESI) m/z476.35[M+1]⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 10.60 (s, 1H), 8.31 (d, J=2.0Hz, 1H), 7.98-7.83 (m, 3H), 7.48 (d, J=8.1 Hz, 2H), 7.36-7.25 (m, 2H),7.11 (qd, J=5.4, 4.8, 3.1 Hz, 3H), 6.98-6.81 (m, 4H), 6.26 (s, 1H), 3.57(dd, J=12.1, 9.6 Hz, 1H), 3.16-2.90 (m, 2H), 2.45 (s, 3H).

Example 133Rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6-dihydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 133F)

Synthesis of rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6-dihydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol (Cpd. No. 133F)

A solution ofrac-N′-((5aR,6S,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylidene)-4-methylbenzenesulfonohydrazide(1, 50. mg, 0.08000 mmol) in dimethylformide (1 mL) and sulfolane (1 mL,0.08000 mmol) was treated with sodium cyanoborohydride (24.32 mg,0.64000 mmol) and the reaction was heated to 110° C. for 4 h. Analysisof the reaction by LCMS showed consumption of the starting material anda mass of the product. Water (0.1 mL) was added and the reaction mixturewas directly purified by prep HPLC then normal phase flash columnchromatography to affordrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6-dihydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 133F) as a white solid. Yield: 0.002 g, 35%; MS (ESI) m/z476.35[M+1]⁺; ¹H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J=1.9 Hz, 1H),7.57-7.45 (m, 1H), 7.42-7.09 (m, 5H), 7.06-6.95 (m, 3H), 6.41 (ddd,J=20.7, 5.9, 2.2 Hz, 2H), 5.32 (s, 6H), 4.52 (t, J=2.2 Hz, 1H).

Example 134 Rac-Methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(Cpd. No. 134F)

Synthesis of(E)-3-(4-bromophenyl)-1-(3-hydroxy-5-methoxypyridin-4-yl)prop-2-en-1-one(3)

To a solution of 1-(3-hydroxy-5-methoxypyridin-4-yl)ethan-1-one (1,200.0 g, 1.197 mol) in methanol (1000 mL), sodium hydroxide (143.7 g,3.59 mmol) was added followed by addition of 4-bromobenzaldehyde (2,221.56 g, 1197.57 mmol). The reaction was heated to reflux for 30 min.After completion, the reaction mass was cooled to room temperature,diluted with water (2000 mL). Solid obtained was filtered and dried. Thesolid obtained was triturated with pentane, filtered and dried undervacuum to afford(E)-3-(4-bromophenyl)-1-(3-hydroxy-5-methoxypyridin-4-yl)prop-2-en-1-one(3) as yellow solid. Yield: 400.0 g, 96%; MS (ESI) m/z 332.0[M−1]⁻.

Synthesis of2-(4-bromophenyl)-3-hydroxy-5-methoxy-4H-pyrano[2,3-c]pyridin-4-one (4)

To a solution of(E)-3-(4-bromophenyl)-1-(3-hydroxy-5-methoxypyridin-4-yl)prop-2-en-1-one(3, 5×40 g, 600.06 mmol) in ethanol (6.0 L) at 0° C., sodium hydroxide(28.8 g, 720.72 mmol) was added followed by the addition of 30% aqueoushydrogen peroxide (429.25 mL, 4204.2 mmol). The reaction mixture washeated at 60° C. for 30 min. After completion, the reaction mixture wascooled and neutralized to pH ˜7 by the addition of 6 M hydrogenchloride. The solid obtained was filtered and dried to get crudecompound. The crude product obtained was triturated with ethanol,filtered and dried under vacuum to afford2-(4-bromophenyl)-3-hydroxy-5-methoxy-4H-pyrano[2,3-c]pyridin-4-one (4)as yellow solid. Yield: 54.0 g, 26.0%; MS (ESI) m/z 348.3[M+1]⁺.

Synthesis of rac-methyl(2R,3R,4R)-2-(4-bromophenyl)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(6)

A solution of2-(4-bromophenyl)-3-hydroxy-5-methoxy-4H-pyrano[2,3-c]pyridin-4-one (4,50.0 g, 144.5 mmol) and methyl cinnamate (5, 234.0 g, 1445.0 mmol) indichloromethane (1200 mL), acetonitrile (600 mL) and methanol (600 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedunder 400 watts UV light for 48 h. After completion, solvent was removedunder reduced pressure and the residue was purified over a plug ofsilica gel eluting the compound with ethyl acetate. The desiredfractions were concentrated under reduced pressure to afford rac-methyl(2R,3R,4R)-2-(4-bromophenyl)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(6) as yellow brown solid. Yield: 70.0 g, crude. MS (ESI) m/z508.42[M−1]⁻.

Synthesis of rac-methyl (4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7)

The crude rac-methyl(2R,3R,4R)-2-(4-bromophenyl)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(6, 70.0 g) was suspended in methanol (700 mL) and treated with 25%sodium methoxide in methanol (222 mL). The reaction was heated at 80° C.for 3 h. After completion, the solvent was removed under reducedpressure. The crude was diluted with ammonium chloride solution, thesolid precipitated was filtered off and washed with water and driedunder vacuum. The solid obtained was stirred in diethyl ether andfiltered off washed with hexane and dried under vacuum to affordrac-methyl(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7) as brown solid. Yield: 60.0 g, 85.7%; MS (ESI) m/z 510.3[M+1]⁺.

Synthesis of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(Cpd. No. 134F)

To a solution of rac-methyl(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7, 60.0 g, 117.6 mmol) in acetonitrile (600 mL) and acetic acid (42.0ml, 705.0 mmol), sodium triacetoxyborohydride (149.6 g, 705.0 mmol) wasadded. The resulting mixture was stirred at room temperature for 4 h.After completion, the reaction mixture was partitioned between saturatedaqueous sodium bicarbonate solution and ethyl acetate. The organic layerwas separated, dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to get the crude product. The crudeproduct was purified by silica gel column chromatography using 5%methanol in dichloromethane as eluents. The desired fractions wereconcentrated under reduced pressure to afford rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(Cpd. No. 134F) as off white solid. Yield: 26.0 g, 43.2%; MS (ESI) m/z512.18[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (s, 1H), 7.98 (s, 1H),7.20 (d, J=8.64 Hz, 2H), 7.08-7.04 (m, 4H), 7.0-6.95 (m, 3H), 5.75 (s,1H), 5.60 (d, J=5.72 Hz, 1H), 4.68 (t, J=6.18 Hz, 1H), 4.33 (d, J=14.36Hz, 1H), 4.07 (dd, J=14.18, 4.7 Hz, 1H), 3.87 (s, 3H), 3.56 (s, 3H).

Example 135Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4,4-difluoropiperidin-1-yl)methanone(Cpd. No. 135F)

Synthesis ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4,4-difluoropiperidin-1-yl)methanone(Cpd. No. 135F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 0.9 g, 1.8 mmol) in dichloromethane (10 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.03 g,5.41 mmol), 1-hydroxybenzotriazole (0.72 g, 5.41 mmol) andN,N-diisopropylethylamine (1.65 mL, 9.12 mmol) were added at 0° C. andstirred for 5 minutes before 4,4-difluoropiperidine hydrochloride (2,1.4 g, 9.12 mmol) was added at same temperature and the mixture wasstirred for 16 h at RT. After completion, reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel column chromatography eluting with 0-4% methanol indichloromethane. The desired fractions were concentrated to affordrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4,4-difluoropiperidin-1-yl)methanone(Cpd. No. 135F) as white solid. Yield: 0.67 g, 67%; MS (ESI) m/z601.01[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 1H), 8.00 (s, 1H),7.20 (d, J=8.4 Hz, 2H), 7.08 (d, J=7.8 Hz, 2H), 7.05-7.01 (m, 2H),6.97-6.91 (m, 3H), 5.73 (s, 1H), 5.29 (d, J=5.6 Hz, 1H), 4.71 (t, J=5.6Hz, 1H), 4.43 (d, J=13.2 Hz, 1H), 4.26 (dd, J=13.6, 5.6 Hz, 1H), 3.97(m, 1H), 3.88 (s, 3H), 3.79-3.69 (m, 2H), 3.38 (m, 1H), 2.20 (m, 2H),1.88 (m, 2H).

Example 136 Rac-Methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(Cpd. No. 136F)

Synthesis of 4-(benzyloxy)-2, 6-dichloropyridine (2)

Sodium hydride (60% in mineral oil) (14.22 g, 355.6 mmol) was added infour portions to a stirred solution of 2,4,6-trichloropyridine (1, 58.98g, 323.3 mmol) in N,N-dimethylformamide (473 mL) at 0° C. undernitrogen. After 5 min benzyl alcohol (33.45 mL, 323.3 mmol) was addeddropwise via addition funnel over 1.5 h. The resulting reaction mixturewas stirred at 0° C. under nitrogen for 2.5 h. Water (5 mL) was addeddropwise very slowly at 0° C., then the reaction mixture was poured intovigorously stirred water (580 mL). Solids were collected by vacuumfiltration, washed with water, and air dried overnight to give 65.44 gof an off-white solid. The solids were dissolved in hot EtOAc andfiltered. The filtrate was concentrated on a rotary evaporator. Theresidue was recrystallized from 2% EtOAc in hexanes to afford4-(benzyloxy)-2,6-dichloropyridine (2) as an off-white solid. Yield:55.10 g, 67%; MS (ESI) m/z 254.0[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ7.48-7.34 (m, 5H), 7.29 (s, 2H), 5.27 (s, 2H).

Synthesis of 4-(benzyloxy)-2-chloro-6-methoxypyridine (3)

Sodium methoxide (25 wt % in methanol) (58.04 mL, 253.9 mmol) was addedto a stirred solution of 4-benzyloxy-2,6-dichloro-pyridine (2, 54.86 g,215.9 mmol) in toluene (910 mL) at room temperature under nitrogen. Theresulting mixture was stirred vigorously and heated at 70° C. under areflux condenser under nitrogen for 9 h. The resulting mixture waspartitioned between water and diethyl ether. The organics were washedwith water and brine, dried over magnesium sulfate, filtered,concentrated on a rotary evaporator, and purified via silica gelchromatography (0.5-1-3% EtOAc in hexanes) to afford4-(benzyloxy)-2-chloro-6-methoxypyridine (3) as a white solid. Yield:35.51 g, 66%; Rf=0.33 (10% EtOAc/hexanes); MS (ESI) m/z 250.2[M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 7.47-7.32 (m, 5H), 6.81 (d, J=1.9 Hz, 1H), 6.46(d, J=1.9 Hz, 1H), 5.20 (s, 2H), 3.81 (s, 3H).

Synthesis of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-ol(4)

Anhydrous acetaldehyde from Sigma Aldrich (00070) was dried over 4Angstrom molecular sieves prior to use. A stirred solution of4-benzyloxy-2-chloro-6-methoxy-pyridine (3, 31.89 g, 127.7 mmol) in THF(480 mL) was cooled with a dry ice/acetone bath to −75° C. for 15 min.n-Butyllithium (2.5 M in hexanes) (61.3 mL, 153.3 mmol) was added slowlyover 10 min. The resulting dark yellow solution was stirred for 30 minat −75° C. and then acetaldehyde (14.35 mL, 255.4 mmol) was added. After10 min saturated aqueous ammonium chloride (45 mL) was added and theresulting mixture was partitioned between water and ethyl acetate. Theorganics were washed with brine, dried over magnesium sulfate, filtered,and concentrated on a rotary evaporator. The crude material was taken upin 10% EtOAc in hexanes and purified via silica gel chromatography(3-6-15% EtOAc in hexanes) to afford1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-ol (4) as acolorless oil which was a 10:1 mixture of regioisomers. Yield: 32.24 g,83%; MS (ESI) m/z 294.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.49-7.31 (m,5H), 6.93 (s, 1H), 5.25 (s, 2H), 5.14 (p, J=6.5 Hz, 1H), 4.61 (d, J=6.1Hz, 1H), 3.84 (s, 3H), 1.39 (d, J=6.7 Hz, 3H). The regioisomers could beseparated by careful chromatography over silica gel.

Synthesis of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-one(5)

Manganese(IV) oxide (26.41 g, 303.8 mmol) was added to a stirredsolution of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-ol(4, 29.75 g, 101.3 mmol) in toluene (400 mL) at room temperature. Theresulting mixture was stirred vigorously and heated at 60° C. under areflux condenser under nitrogen. After 24 h more manganese(IV) oxide(26.41 g, 303.8 mmol) was added and heating was continued at 60° C. At48 h more manganese(IV) oxide (20.00 g, 230.0 mmol) was added andheating was continued at 60° C. At 73 h more manganese(IV) oxide (10.00g, 115.0 mmol) was added and heating was continued at 60° C. for a totalreaction time of 90 h. After cooling to room temperature the reactionmixture was filtered through Celite and the filter cake washedthoroughly with EtOAc. The filtrate was concentrated on a rotaryevaporator and purified via silica gel chromatography (1-4-10%EtOAc/hexanes) to afford1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-one (5) as awhite solid. Yield: 23.36 g, 79%; MS (ESI) m/z 292.2[M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 7.47-7.32 (m, 5H), 7.11 (s, 1H), 5.28 (s, 2H), 3.85 (s,3H), 2.38 (s, 3H).

Synthesis of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (6)

1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-one (5, 23.35 g,80.04 mmol) was dissolved in ethyl acetate (600 mL) with stirring in a 2L round bottom flask. A combination vacuum/nitrogen/hydrogen manifoldwas attached and the atmosphere in the flask was removed and replacedwith argon. 10% palladium on carbon (188. mg, 1.88 mmol) was added andthe atmosphere in the flask was removed and replaced with hydrogen. Theresulting mixture was stirred vigorously at room temperature underhydrogen for 3 h. The reaction mixture was filtered through Celite andthe filter cake washed thoroughly with EtOAc. The filtrate wasconcentrated on a rotary evaporator and purified via silica gelchromatography (1% ethyl acetate in hexanes isocratic) to afford1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (6) as a whitesolid. Yield: 14.15 g, 88%; MS (ESI) m/z 202.2[M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 13.02 (s, 1H), 6.70 (s, 1H), 3.91 (s, 3H), 2.53 (s, 3H).

Synthesis of(E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one(8)

To a 1 L round bottom flask with a stirbar was added sequentially:1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (6, 14.13 g,70.09 mmol) 4-bromobenzaldehyde (7, 13.34 g, 72.13 mmol),N,N-dimethylformamide (170 mL), and then sodium methoxide (25 wt % inmethanol) (48.04 mL, 210.1 mmol). The reaction mixture was stirredvigorously and heated at 50° C. under a reflux condenser for 20 min. Thereaction mixture is initially clear and light yellow, but then a lot ofsolids precipitated. More N,N-dimethylformamide (50 mL) was added tokeep the reaction stirring. The reaction mixture was poured onto avigorously stirred mixture of 1 N hydrochloric acid in water (210 mL,210 mmol) and ice water (500 mL). The resulting light yellow mixture wasstirred vigorously for 10 min and then solids were collected by vacuumfiltration. The solids were washed with water and dried under highvacuum to afford(E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one(8) as a yellow solid. Yield: 25.83 g, 100%; MS (ESI) m/z 368.0,369.9[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.72-7.67 (m, 2H), 7.65-7.59(m, 2H), 7.40 (d, J=16.2 Hz, 1H), 7.17 (d, J=16.1 Hz, 1H), 6.60 (s, 1H),3.81 (s, 3H).

Synthesis of2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one(9)

10% aqueous sodium hydroxide (18.1 mL, 49.78 mmol) was added to astirred mixture (not all dissolved) of(E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one(8, 8.31 g, 22.54 mmol) in ethanol (160 mL) and dichloromethane (40 mL)cooled with a room temperature water bath. After 1 min 30% aqueoushydrogen peroxide (16.19 mL, 158.5 mmol) was added. The reaction mixturewas stirred vigorously while cooled with a room temperature water bathfor 1 h. The reaction mixture was diluted with dichloromethane, pouredonto saturated aqueous ammonium chloride (250 mL), and extracted threetimes with dichloromethane. The organics were concentrated on a rotaryevaporator. The residual solids were shaken in a separatory funnel withdichloromethane (1 L) and saturated aqueous ammonium chloride (250 mL).The layers were separated and the water layer extracted twice withdichloromethane. The combined organics were dried over Na₂SO₄, filtered,and concentrated on a rotary evaporator. 10% ethyl acetate in hexanes(100 mL) was added to the residue and the resulting mixture was heatedto reflux with a heat gun. The mixture was capped and let stand 1 h atroom temperature. Solids were collected by vacuum filtration, washedwith 10% ethyl acetate in hexanes, and dried under high vacuum to afford2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one(9) as an orange solid. Yield: 1.61 g, 19%; MS (ESI) m/z 382.0,384.0[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.01 (s, 1H), 8.15-8.09 (m,2H), 7.80-7.75 (m, 2H), 7.55 (s, 1H), 4.02 (s, 3H).

Synthesis of rac-methyl(3S,4S,5R)-2-(4-bromophenyl)-8-chloro-5,10,10-trihydroxy-6-methoxy-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate(11)

To a 500 mL round bottom flask was added sequentially: a stir bar,2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one(9, 1.61 g, 4.21 mmol), methyl cinnamate(10, 6.83 g, 42.1 mmol),chloroform (80 mL), and trifluoroethanol (80 mL). The reaction mixturewas stirred vigorously and irradiated with 450 W UV light while beingcooled with a 0° C. cold bath for 5 h. The reaction mixture was dilutedwith 3% triethylamine in ethyl acetate (15 mL), concentrated on a rotaryevaporator with silica gel, and dried under high vacuum overnight. Theresidue was loaded into a loading column and purified via silica gelchromatography (0-5-100% EtOAc/hexanes) (column was pre-equilibratedwith 10% EtOAc in hexanes with 3% triethylamine prior to equilibrationwith 0% hexanes) to afford 1.67 g of impure rac-methyl(3S,4S,5R)-2-(4-bromophenyl)-8-chloro-5,10,10-trihydroxy-6-methoxy-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate(11) an orange residue which was taken on to the next step withoutfurther purification. MS (ESI) m/z 562.3, 564.2 [M]+.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-1-methoxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(12)

Sodium methoxide (25 wt. % in methanol) (2.03 mL, 8.89 mmol) was addedto a stirred solution of impure rac-methyl(3S,4S,5R)-2-(4-bromophenyl)-8-chloro-5,10,10-trihydroxy-6-methoxy-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate(11, 1.67 g, 2.97 mmol) in methanol (60 mL) at room temperature underargon. The clear yellow solution changed to dark orange colored. Thereaction mixture was heated at 60° C. under a reflux condenser underargon for 40 min and then most of the solvent was removed on a rotaryevaporator. The residue was partitioned between saturated aqueousammonium chloride and ethyl acetate. The organics were washed withbrine, dried over magnesium sulfate, filtered, concentrated on a rotaryevaporator, and dried under high vacuum to afford impure rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-1-methoxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(12) as an orange residue. Yield: 1.57 g; MS (ESI) m/z 544.0,546.1[M+1]⁺. This material was carried on without further purification.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(Cpd. No. 136F)

To a stirred solution of impure rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-1-methoxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(12, 1.57 g, 2.88 mmol) in MeCN (50 mL) at room temperature was addedacetic acid (1.65 mL, 28.8 mmol) and then sodium triacetoxyborohydride(3.05 g, 14.4 mmol). The resulting reaction mixture was stirredvigorously at room temperature under argon for 40 min. Saturated aqueousammonium chloride (20 mL) was added slowly dropwise and the resultingmixture was partitioned between water and ethyl acetate. The organicswere washed with saturated aqueous sodium bicarbonate and then brine,dried over magnesium sulfate, filtered, concentrated on a rotaryevaporator and purified via silica gel chromatography (12-22%EtOAc/hexanes) to afford rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(Cpd. No. 136F) as a slightly yellow foam-solid. Yield: 631 mg, 27% overthree steps; MS (ESI) m/z 546.1, 548.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆)δ 7.24-7.19 (m, 2H), 7.09-6.92 (m, 8H), 5.70-5.64 (m, 2H), 4.62 (t,J=5.4 Hz, 1H), 4.31 (d, J=13.9 Hz, 1H), 4.09 (dd, J=14.0, 4.9 Hz, 1H),3.83 (s, 3H), 3.57 (s, 3H).

Example 137Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(Cpd. No. 137F)

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (2)

To a stirred solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(1, 1.09 g, 1.99 mmol) in methanol (40 mL) was added water (4 mL) andthen lithium hydroxide (477 mg, 19.9 mmol). The resulting yellowreaction mixture was stirred vigorously and heated at 50° C. under areflux condenser for 4.5 h. The reaction mixture was cooled with a 0° C.cold bath and 1 N hydrochloric acid in water (19.9 mL, 19.9 mmol) wasadded with vigorous stirring. A few more drops of 1 N hydrochloric acidwas added to make the mixture slightly acidic. Most of the methanol wasremoved on a rotary evaporator. The residue was extracted three timeswith dichloromethane. The combined organics were washed with brine,dried over magnesium sulfate, filtered, concentrated on a rotaryevaporator, and dried under high vacuum at 40° C. overnight to affordcruderac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (2) as a white solid with yellow impurity. Yield: 961 mg, 90%; MS(ESI) m/z 532.1, 534.0[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H),7.24-7.18 (m, 2H), 7.06 (m, 2H), 7.03-6.94 (m, 5H), 6.93 (s, 1H), 5.62(d, J=8.3 Hz, 2H), 4.62 (t, J=5.3 Hz, 1H), 4.29 (d, J=13.9 Hz, 1H), 3.95(dd, J=14.0, 5.0 Hz, 1H), 3.84 (s, 3H).

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(Cpd. No. 137F)

HATU (686 mg, 1.80 mmol) was added to a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (2, 915 mg, 1.72 mmol) in N,N-dimethylformamide (15 mL) at roomtemperature under argon. After 2 min N,N-diisopropylethylamine (0.45 mL,2.58 mmol) was added. The resulting reaction mixture was stirred at roomtemperature under argon for 20 min. Dimethylamine (2 M solution in THF)(2.58 mL, 5.15 mmol) was added and the reaction mixture was stirred atroom temperature under argon for 3 h. The reaction mixture was dilutedwith 90% ethyl acetate in hexanes, washed three times with water, oncewith brine, dried over magnesium sulfate, filtered, concentrated on arotary evaporator, and purified via silica gel chromatography (30-100%EtOAc/hexanes) to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(Cpd. No. 137F) as a white foam-solid. Yield: 917 mg, 95%; MS (ESI) m/z559.1, 561.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.25-7.20 (m, 2H),7.07-7.00 (m, 4H), 6.99-6.93 (m, 2H), 6.89 (dt, J=8.2, 1.2 Hz, 2H), 5.62(s, 1H), 5.19 (d, J=5.7 Hz, 1H), 4.69 (t, J=5.5 Hz, 1H), 4.41 (d, J=13.4Hz, 1H), 4.18 (dd, J=13.5, 5.2 Hz, 1H), 3.84 (s, 3H), 3.27 (s, 3H), 2.77(s, 3H).

Example 138Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 138F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6, 7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 138F)

Borane dimethyl sulfide complex (1.47 mL, 15.5 mmol) was added to astirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(1, 866 mg, 1.55 mmol) in THF (30 mL) at room temperature under a refluxcondenser under argon. Some bubbling was observed. The reaction mixturewas heated at 40° C. under a reflux condenser under argon for 3 h. Aftercooling to room temperature, wet methanol (20 mL) was added dropwiseslowly. The resulting clear colorless reaction mixture was stirredvigorously and heated at 65° C. under a reflux condenser under argon for36 h. The reaction mixture was loaded onto five 2 g Strata X-C ionexchange columns from Phenomenex. The columns were washed sequentiallywith acetonitrile, methanol, and then a mixture of 5% ammonium hydroxidein methanol/dichloromethane. Eluent containing the desired product wasconcentrated on a rotary evaporator and dried under high vacuum at 40°C. to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 138F) as a white solid. Yield: 742 mg, 88%; MS (ESI) m/z545.2, 547.3; 1H NMR (400 MHz, DMSO-d₆) δ 7.26-7.21 (m, 2H), 7.13-7.05(m, 4H), 7.04-6.94 (m, 3H), 6.86 (s, 1H), 5.56 (s, 1H), 5.15 (s, 1H),4.43 (s, 1H), 3.84 (s, 3H), 3.70 (d, J=14.1 Hz, 1H), 3.08 (ddt, J=14.0,10.0, 3.6 Hz, 1H), 2.56 (m, 1H), 2.19 (s, 6H), 1.94 (d, J=11.1 Hz, 1H).

Example 139(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 139F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 139F)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 165 mg, 0.300 mmol), zinc cyanide (213 mg, 1.81 mmol), zinc powder(19.8 mg, 0.300 mmol), N,N-dimethylformamide (0.9 mL), and water (0.09mL) were combined in a microwave vial with a stirbar. The resultingmixture was sparged with argon gas for 5 min. Pd₂dba₃ (27.7 mg, 0.030mmol) and dppf (33.5 mg, 0.060 mmol) were added and the resultingmixture was sparged with argon gas for 5 min. The reaction mixture wassealed, stirred, and microwaved at 120° C. for 2 h. The reaction mixturewas diluted with DMSO and methanol, filtered, and purified viapreparatory HPLC (15-35% acetonitrile in water with 0.1% TFA). Fractionscontaining the desired product were loaded onto three 2 g Strata X-C ionexchange columns from Phenomenex. The columns were washed sequentiallywith water, acetonitrile, methanol, and then a mixture of 10% ammoniumhydroxide, 20% dichloromethane, and 70% methanol. Fractions containingthe desired product were combined, concentrated on a rotary evaporator,and dried under high vacuum at 40° C. to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrileas a white solid. Yield: 91.6 mg, 63%; The enantiomers were separated bychiral preparative SFC [Chiralpak IG (4.6×250) mm, 5μ] usingCO₂:EtOH:TEA (60:40:0.1) Mobile phase. Peak 1 (Cpd. No. 139F), [α]_(D)−36.4° (c 0.3, CHCl₃), R_(t)=1.52 min, ee>99%. MS (ESI) m/z483.15[M+1]⁺; UPLC: 99.75; 1H NMR (400 MHz, DMSO-d₆) δ 7.61-7.51 (m,3H), 7.37 (d, J=8.2 Hz, 2H), 7.10-7.06 (m, 2H), 7.02-6.98 (m, 3H), 5.86(s, 1H), 5.35 (bs, 1H), 4.51 (s, 1H), 3.89 (s, 3H), 3.79 (d, J=13.9 Hz,1H), 3.17-3.16 (m, 1H), 2.62-2.60 (m, 1H), 2.23 (bs, 6H). 1.98 (bs, 1H).Peak 2, SOR (not recorded, solubility issues) R_(t)=2.04 min, ee>99%. MS(ESI) m/z 483.15[M+1]⁺; UPLC: 99.78%. ¹H NMR (400 MHz, DMSO-d₆) δ7.54-7.50 (m, 3H), 7.35 (d, J=8.2 Hz, 2H), 7.09-7.06 (m, 2H), 7.01-6.88(m, 3H), 5.85 (s, 1H), 5.42 (bs, 1H), 4.59 (d, J=3.0 Hz, 1H), 3.89 (s,3H), 3.77 (d, J=14.0 Hz, 1H), 3.18-3.16 (m, 1H), 2.58-2.50 (m, 1H), 2.21(s, 6H), 1.96 (d, J=10.3 Hz, 1H).

Example 1404-((5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 140F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol (2)

tert-Butyldimethylsilyl trifluoromethanesulfonate (0.82 mL, 3.56 mmol)was added to a stirred mixture (not all dissolved) ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 648 mg, 1.19 mmol) and 2,6-lutidine (0.83 mL, 7.12 mmol) in DCE (10mL) at room temperature under argon. (All solids dissolved) The reactionmixture was sealed and stirred at room temperature for 11 h. Thereaction mixture was loaded directly onto a silica gel loading columnand purified via silica gel chromatography (10-50% EtOAc/hexanes) toaffordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(2) as a white solid. Yield: 677 mg, 86%; MS (ESI) m/z 661.3[M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 7.18 (d, J=8.7 Hz, 2H), 7.12-6.96 (m, 7H), 6.89(s, 1H), 5.87 (s, 1H), 4.46 (d, J=2.8 Hz, 1H), 4.04-3.97 (m, 1H), 3.79(s, 3H), 3.25 (t, J=12.1 Hz, 1H), 2.21 (s, 6H), 1.92 (d, J=12.0 Hz, 1H),0.69 (s, 9H), 0.12 (s, 3H), −0.30 (s, 3H).

Synthesis ofrac-1-((5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)-N,N-dimethylmethanamine(3)

Trimethylsilyl trifluoromethanesulfonate (0.26 mL, 1.45 mmol) was addedto a stirred mixture ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(2, 640 mg, 0.970 mmol) and N,N-diisopropylethylamine (0.51 mL, 2.91mmol) in DCE (10 mL) at room temperature under argon. The reactionmixture was heated at 40° C. under a reflux condenser under argon for2.5 h. More N,N-diisopropylethylamine (0.51 mL, 2.91 mmol) was addedfollowed by trimethylsilyl trifluoromethanesulfonate (0.26 mL, 1.45mmol). The reaction mixture was heated at 40° C. under a refluxcondenser under argon for 1.5 h. The reaction mixture was partitionedbetween dichloromethane and saturated aqueous sodium bicarbonate. Thewater layer was extracted with dichloromethane. The combined organicswere concentrated to dryness and purified via silica gel chromatography(1-20% EtOAc/hexanes) to affordrac-1-((5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)-N,N-dimethylmethanamine(3) as a white solid at 90% purity. Yield: 649 mg, 81%; MS (ESI) m/z733.2[M+1]⁺.

Synthesis ofrac-4-((5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(4)

p-Toluenesulfonyl cyanide from Aldrich (248835) was recrystallized fromtoluene/hexanes, dissolved in THF, and dried over 4 Angstrom molecularsieves for prior to use.Rac-1-((5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)-N,N-dimethylmethanamine(3, 467 mg, 0.640 mmol) was dissolved in THF (6 mL) with stirring underargon. The resulting colorless solution was cooled to −78° C. with a dryice/acetone bath for 15 min. n-Butyllithium (2.5 M in hexane) (0.29 mL,0.73 mmol) was added dropwise slowly. The reaction mixture was stirredfor 30 min at −78° C. under argon. p-Toluenesulfonyl cyanide (2 M inTHF) (0.48 mL, 0.96 mmol) was added and the resulting mixture wasstirred at −78° C. under argon for 25 min. Saturated aqueous ammoniumchloride (2 mL) was added and the resulting mixture was partitionedbetween water and ethyl acetate. The organics were washed with brine,dried over magnesium sulfate, filtered, concentrated, and purified viasilica gel chromatography (10-25% EtOAc/hexanes) to afford impurerac-4-((5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(4) as a white foam solid. Yield: 296 mg; MS (ESI) m/z 678.4[M+1]⁺. Thismaterial was taken on to the next step without further purification.

Synthesis of4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 140F)

Tetrabutylammonium fluoride (1 M in THF) (2.60 mL, 2.60 mmol) was addedto a stirred solution ofrac-4-((5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(4, 294 mg, 0.430 mmol) in THF (5 mL). The reaction mixture was sealed,stirred, and heated at 40° C. for 17 h. The solvent was removed on arotary evaporator. The residue was taken up in DMSO and methanol,filtered, and purified via preparatory HPLC (25-35% acetonitrile inwater with 0.1% TFA). Fractions containing the desired product wereloaded onto a Strata X-C ion exchange column from Phenomenex. The columnwas washed sequentially with water, acetonitrile, methanol, and then 5%ammonium hydroxide in methanol/dichloromethane. Eluent containing thedesired product was concentrated on a rotary evaporator. The residue wastaken up in 50% acetonitrile in water, sonicated for a few seconds, andthen lyophilized to dryness to affordrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrileas a white solid. Yield: 176 mg, 56% over two steps; The enantiomerswere separated by chiral preparative SFC [Chiralpak IG (4.6×250) mm, 5μ]using CO₂:EtOH:TEA (60:40:0.2) Mobile phase. Peak 1 (320 mg), [α]_(D)+45° (c 0.3, CHCl₃), R_(t)=1.90 min, ee>99%. MS (ESI) m/z 492.2 [M+1]⁺;UPLC: 99.88%. ¹H NMR (400 MHz, DMSO-d₆) δ 7.51 (d, J=8.2 Hz, 2H), 7.35(d, J=8.36 Hz, 2H), 7.09-7.05 (m, 2H), 7.01-6.97 (m, 3H), 6.89 (s, 1H),5.67 (s, 1H), 5.27 (brs, 1H), 4.44 (s, 1H), 3.84 (s, 3H), 3.76 (d,J=14.0 Hz, 1H), 3.18-3.14 (m, 1H), 2.57 (m, 1H), 2.22 (s, 6H), 1.99(brs, 1H); Peak 2 (Cpd. No. 140F, 478 mg), [α]_(D) −41.0° (c 0.3,CHCl₃), R_(t)=3.76 min, ee>99%. MS (ESI) m/z 492.24[M+1]⁺; UPLC: 99.68%.¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (d, J=8.48 Hz, 2H), 7.34 (d, J=8.4 Hz,2H), 7.09-7.05 (m, 2H), 7.01-6.97 (m, 3H), 6.88 (s, 1H), 5.66 (s, 1H),5.22 (brs, 1H), 4.44 (s, 1H), 3.84 (s, 3H), 3.76 (d, J=14.0 Hz, 1H),3.17-3.14 (m, 1H), 2.57 (m, 1H), 2.20 (s, 6H), 1.97 (d, J=12.08 HZ, 1H).

Example 141Rac-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 141F)

Synthesis ofrac-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 141F)

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(1, 27.2 mg, 0.060 mmol), sodium bicarbonate (9.3 mg, 0.11 mmol), andmethanol (7 mL) were combined in a 25 mL round bottom flask with astirbar. The mixture was sonicated at room temperature for 1 min todissolve the starting material. A combination vacuum/hydrogen/argonmanifold was attached and the atmosphere in the flask was removed andreplaced with argon twice. 10% palladium on activated charcoal (5.9 mg,0.010 mmol) was added and the atmosphere in the flask was removed andreplaced with hydrogen twice. The reaction mixture was stirredvigorously at room temperature under a hydrogen balloon for 10 h. Thereaction mixture was filtered through a syringe filter and the solventwas removed on a rotary evaporator. The residue was taken up in DMSO andmethanol and purified via preparatory HPLC (10-30% acetonitrile in waterwith 0.1% TFA). Fractions containing the desired product were loadedonto a Strata X-C ion exchange column from Phenomenex. The column waswashed sequentially with water, acetonitrile, methanol, and then 5%ammonium hydroxide in methanol. Eluent containing the desired productwas concentrated on a rotary evaporator. The residue was taken up in 50%acetonitrile in water and lyophilized to dryness to affordrac-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 141F) as a white solid. Yield: 11.7 mg, 46%; MS (ESI) m/z458.5[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (d, J=5.7 Hz, 1H), 7.51(d, J=8.7 Hz, 2H), 7.40-7.34 (m, 2H), 7.12-7.04 (m, 2H), 7.03-6.95 (m,3H), 6.75 (d, J=5.7 Hz, 1H), 5.58 (s, 1H), 5.11 (s, 1H), 4.50 (d, J=4.1Hz, 1H), 3.85 (s, 3H), 3.74 (d, J=14.1 Hz, 1H), 3.17 (m, 1H), 2.62 (m,1H), 2.27 (s, 6H), 2.06 (m, 1H).

Example 142Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 142F)

Synthesis ofrac-1-((5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-5a-(4-chlorophenyl)-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)-N,N-dimethylmethanamine(2)

Hexachloroethane from Aldrich was dissolved in THF and dried over 4Angstrom molecular sieves for 2 hours prior to use.Rac-1-((5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)-N,N-dimethylmethanamine(1, 205 mg, 0.280 mmol) was dissolved in THF (3 mL) with stirring underargon. The resulting colorless solution was cooled to −78° C. with a dryice/acetone bath for 15 min. n-Butyllithium (2.5 M in hexane) (0.15 mL,0.36 mmol) was added dropwise slowly. The reaction mixture was stirredfor 30 min at −78° C. under argon and then hexachloroethane (0.42 M inTHF) (1.07 mL, 0.450 mmol) was added and the resulting mixture wasstirred at −78° C. under argon for 45 min. Saturated aqueous ammoniumchloride (1 mL) was added and the reaction mixture was warmed to roomtemperature with stirring. The resulting mixture was partitioned betweenwater and ethyl acetate. The organics were washed with brine, dried overmagnesium sulfate, filtered, concentrated on a rotary evaporator, andpurified via silica gel chromatography (5-20% EtOAc/hexanes) to affordrac-1-((5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-5a-(4-chlorophenyl)-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)-N,N-dimethylmethanamine(2) as a white solid. Yield: 154 mg, 80%; MS (ESI) m/z 687.3[M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 7.12-6.95 (m, 10H), 4.49 (d, J=3.3 Hz, 1H),3.95 (d, J=13.0 Hz, 1H), 3.79 (s, 3H), 3.19 (m, 1H), 2.18 (s, 6H), 2.00(m, 1H), 0.67 (s, 9H), 0.11 (s, 3H), −0.16 (s, 9H), −0.26 (s, 3H).

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6, 7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 142F)

Tetrabutylammonium fluoride (1 M in THF) (0.97 mL, 0.97 mmol) was addedto a stirred solution ofrac-1-((5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-5a-(4-chlorophenyl)-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)-N,N-dimethylmethanamine(2, 111 mg, 0.160 mmol) in THF (3 mL). The reaction mixture was sealed,stirred, and heated at 40° C. for 14 h. The solvent was removed on arotary evaporator. The residue was taken up in DMSO and methanol,filtered, and purified via preparatory HPLC (15-47% acetonitrile inwater with 0.1% TFA). Fractions containing the desired product wereloaded onto a Strata X-C ion exchange column from Phenomenex. The columnwas washed sequentially with water, acetonitrile, methanol, and then 5%ammonium hydroxide in methanol/dichloromethane. Eluent containing thedesired product was concentrated on a rotary evaporator, and dried underhigh vacuum at 40° C. to affordrac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 142F) as a white solid. Yield: 40.0 mg, 49%; MS (ESI) m/z501.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.16-7.11 (m, 2H), 7.09-7.01(m, 4H), 7.01-6.90 (m, 3H), 6.83 (s, 1H), 5.54 (s, 1H), 5.17 (s, 1H),4.41 (d, J=4.1 Hz, 1H), 3.81 (s, 3H), 3.66 (d, J=14.0 Hz, 1H), 3.07 (m,1H), 2.54 (m, 1H), 2.20 (s, 6H), 1.95 (m, 1H).

Example 143Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 143F)

Synthesis of7-chloro-2-(4-(difluoromethyl)phenyl)-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one(2)

10% aqueous sodium hydroxide (3.87 mL, 10.7 mmol) was added to a stirredmixture (not all dissolved) of(E)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)-3-(4-(difluoromethyl)phenyl)prop-2-en-1-one(1, 1.64 g, 4.83 mmol) in ethanol (32 mL) and dichloromethane (8 mL)cooled with a room temperature water bath. After 1 min 30% aqueoushydrogen peroxide (3.46 mL, 33.9 mmol) was added. The reaction mixturewas stirred vigorously while cooled with a room temperature water bathfor 1.5 h. The reaction mixture was diluted with dichloromethane, pouredonto saturated aqueous ammonium chloride (50 mL), and extracted threetimes with dichloromethane. The organics were concentrated on a rotaryevaporator. The residual solids were shaken in a separatory funnel withdichloromethane (200 mL) and saturated aqueous ammonium chloride (50mL). The layers were separated and the water layer extracted twice withdichloromethane. The combined organics were dried over Na₂SO₄, filtered,and concentrated on a rotary evaporator. The residue was triturated withmethanol at room temperature and dried under high vacuum to afford7-chloro-2-(4-(difluoromethyl)phenyl)-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one(2) as a tan solid. Yield: 231 mg, 14%; MS (ESI) m/z 354.2[M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 10.07 (s, 1H), 8.34-8.28 (m, 2H), 7.79-7.73 (m,2H), 7.56 (s, 1H), 7.12 (t, J=55.7 Hz, 1H), 4.03 (s, 3H).

Synthesis of rac-methyl(3S,4S,5R)-8-chloro-2-(4-(difluoromethyl)phenyl)-5,10,10-trihydroxy-6-methoxy-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate (4)

To a 100 mL round bottom flask was added sequentially: a stir bar,7-chloro-2-(4-(difluoromethyl)phenyl)-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one(2, 257 mg, 0.730 mmol), methyl cinnamate (3, 1.18 g, 7.27 mmol),chloroform (12 mL), and trifluoroethanol (12 mL). (All material is notdissolved). The reaction mixture was stirred vigorously and irradiatedwith 450 W UV light while being cooled with a 0° C. cold bath for 3 h.The reaction mixture was diluted with 3% triethylamine in ethyl acetate(15 mL), concentrated on a rotary evaporator with silica gel, and driedunder high vacuum overnight. The residue was loaded into a loadingcolumn and purified via silica gel chromatography (0-5-100%EtOAc/hexanes) to afford impure rac-methyl(3S,4S,5R)-8-chloro-2-(4-(difluoromethyl)phenyl)-5,10,10-trihydroxy-6-methoxy-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate(4) as an orange residue. Yield: 280 mg; MS (ESI) m/z 534.3 [M]⁺. Thismaterial was taken on to the next step without further purification.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8a-hydroxy-1-methoxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(5)

Sodium methoxide (25 wt. % in methanol) (0.34 mL, 1.49 mmol) was addedto a stirred solution of rac-methyl(3S,4S,5R)-8-chloro-2-(4-(difluoromethyl)phenyl)-5,10,10-trihydroxy-6-methoxy-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate(4, 273 mg, 0.490 mmol) in methanol (10 mL) at room temperature underargon. The clear yellow solution changed to dark orange colored. Thereaction mixture was heated at 60° C. under a reflux condenser underargon for 40 min and then most of the solvent was removed on a rotaryevaporator. The residue was partitioned between saturated aqueousammonium chloride and ethyl acetate. The organics were washed withbrine, dried over magnesium sulfate, filtered, concentrated on a rotaryevaporator, and dried under high vacuum to afford rac-methyl(5aR,6S,7R,8aR)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8a-hydroxy-1-methoxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(5) as a yellow residue. Yield: 240 mg; MS (ESI) m/z 534.1[M+1]⁺. Thismaterial was carried on without further purification.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(6)

To a stirred solution of rac-methyl(5aR,6S,7R,8aR)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8a-hydroxy-1-methoxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(5, 264 mg, 0.510 mmol) in MeCN (9 mL) at room temperature was addedacetic acid (0.29 mL, 5.12 mmol) and then sodium triacetoxyborohydride(542 mg, 2.56 mmol). The resulting reaction mixture was stirredvigorously at room temperature for 40 min. Saturated aqueous ammoniumchloride (5 mL) was added slowly dropwise and the resulting mixture waspartitioned between water and ethyl acetate. The organics were washedwith saturated aqueous sodium bicarbonate and then brine, dried overmagnesium sulfate, filtered, concentrated on a rotary evaporator andpurified via silica gel chromatography (12-22% EtOAc/hexanes) to affordrac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(6) as a slightly yellow solid. Yield: 100 mg, 27% over three steps; MS(ESI) m/z 518.2[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.22 (s, 4H),7.07-7.00 (m, 2H), 6.99-6.92 (m, 4H), 6.80 (t, J=55.9 Hz, 1H), 5.71-5.66(m, 2H), 4.67-4.62 (m, 1H), 4.33 (d, J=14.1 Hz, 1H), 4.14 (dd, J=14.0,4.9 Hz, 1H), 3.83 (s, 3H), 3.58 (s, 3H).

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (7)

To a stirred mixture (not all dissolved) of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(6, 98.2 mg, 0.190 mmol) in methanol (4 mL) was added water (0.4 mL) andthen lithium hydroxide (45.4 mg, 1.90 mmol). The resulting yellowreaction mixture was stirred and heated at 50° C. under a refluxcondenser under argon for 3 h. The reaction mixture was cooled with a 0°C. cold bath and 1 N hydrochloric acid in water (1.89 mL, 1.89 mmol) wasadded with vigorous stirring. A few more drops of 1 N hydrochloric acidwas added to make the mixture slightly acidic. Most of the methanol wasremoved on a rotary evaporator. The residue was extracted three timeswith dichloromethane. The combined organics were washed with brine,dried over magnesium sulfate, filtered, concentrated on a rotaryevaporator and dried under high vacuum at 40° C. overnight to affordcruderac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (7) as a white solid with yellow impurity. Yield: 84.3 mg, 88%; MS(ESI) m/z 504.2[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(8)

HATU (66.6 mg, 0.180 mmol) was added to a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (7, 84.1 mg, 0.170 mmol) in N,N-dimethylformamide (1.5 mL) at roomtemperature under argon. After 2 min N,N-diisopropylethylamine (0.04 mL,0.250 mmol) was added. The resulting reaction mixture was capped andstirred at room temperature for 20 min. Dimethylamine (2 M solution inTHF) (0.25 mL, 0.50 mmol) was added and the reaction mixture was cappedand stirred at room temperature for 40 min. The reaction mixture wasdiluted with ethyl acetate and diethyl ether, washed three times withwater, once with brine, dried over magnesium sulfate, filtered,concentrated on a rotary evaporator, and purified via silica gelchromatography (20-100% EtOAc/hexanes) to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(8) as a white foam-solid. Yield: 80.1 mg, 90%; MS (ESI) m/z531.3[M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 143F)

Borane dimethyl sulfide complex (0.14 mL, 1.51 mmol) was added to astirred solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(8, 80.1 mg, 0.150 mmol) in THF (3.5 mL) at room temperature under areflux condenser under argon. Some bubbling was observed. The reactionmixture was heated at 40° C. under a reflux condenser under argon for3.5 h. After cooling to room temperature, wet methanol (2.5 mL) wasadded dropwise slowly. The resulting clear colorless reaction mixturewas stirred vigorously and heated at 65° C. under a reflux condenserunder argon for 43 h. The reaction mixture was loaded onto a 2 g StrataX-C ion exchange column from Phenomenex. The column was washedsequentially with acetonitrile, methanol, and then 5% ammonium hydroxidein dichloromethane/methanol. Eluent containing the desired product wasconcentrated on a rotary evaporator. The residue was taken up in 50%acetonitrile in water (not all dissolved), sonicated for a few seconds,and then lyophilized to dryness to affordrac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 143F) as a white solid. Yield: 67.8 mg, 87%; MS (ESI) m/z517.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.30 (d, J=8.7 Hz, 2H), 7.24(dt, J=8.6, 1.1 Hz, 2H), 7.09-7.02 (m, 2H), 7.01-6.93 (m, 3H), 6.88 (s,1H), 6.85 (t, J=55.9 Hz, 1H), 5.58 (s, 1H), 5.16 (s, 1H), 4.46 (d, J=4.2Hz, 1H), 3.84 (s, 3H), 3.72 (d, J=14.1 Hz, 1H), 3.14 (ddt, J=14.0, 10.1,3.7 Hz, 1H), 2.60-2.52 (m, 1H), 2.21 (s, 6H), 1.99-1.92 (m, 1H).

Example 144Rac-(5aR,6S,7S,8R,8aS)-3-chloro-7-((dirnethylarnino)rnethyl)-1-rnethoxy-6-phenyl-5a-(4-(trifluorornethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No. 144F)

Synthesis of(E)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(3)

Sodium methoxide (25 wt % in methanol) (65.8 mL, 288 mmol) was added toa stirred mixture (not all dissolved) of1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (1, 19.33 g,95.88 mmol) and 4-(trifluoromethyl)benzaldehyde (2, 15.8 mL, 116 mmol)in methanol (300 mL) with stirring at room temperature. The resultingclear yellow reaction mixture was heated at 40° C. under a refluxcondenser under argon for 18.5 h. The reaction mixture was poured onto astirred mixture of 1 N hydrochloric acid in water (288 mL, 288 mmol) andice water (1 L). The resulting mixture was stirred vigorously for 5 min.Solids were collected by vacuum filtration, washed with water, and thenhexanes, and dried under high vacuum to afford(E)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(3) as a light yellow solid. Yield: 29.24 g, 85%; MS (ESI) m/z358.0[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.99-7.93 (m, 2H), 7.81-7.74(m, 2H), 7.51 (d, J=16.2 Hz, 1H), 7.27 (d, J=16.2 Hz, 1H), 6.61 (s, 1H),3.82 (s, 3H).

Synthesis of7-chloro-3-hydroxy-5-methoxy-2-(4-(trifluoromethyl)phenyl)-4H-pyrano[3,2-c]pyridin-4-one(4)

10% aqueous sodium hydroxide (10.2 mL, 27.9 mmol) was added to a stirredmixture (not all dissolved) of(E)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(3, 4.53 g, 12.66 mmol) in ethanol (80 mL) and dichloromethane (20 mL)cooled with a room temperature water bath. After 1 min 30% aqueoushydrogen peroxide (9.07 mL, 88.8 mmol) was added. The reaction mixturewas stirred vigorously while cooled with a room temperature water bathfor 2 h. The reaction mixture was diluted with dichloromethane, pouredonto saturated aqueous ammonium chloride (125 mL), and extracted threetimes with dichloromethane. The organics were concentrated on a rotaryevaporator. The residue was triturated with methanol at room temperatureand dried under high vacuum to afford7-chloro-3-hydroxy-5-methoxy-2-(4-(trifluoromethyl)phenyl)-4H-pyrano[3,2-c]pyridin-4-one(4) as a light yellow solid. Yield: 319 mg, 7%; MS (ESI) m/z372.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.24 (s, 1H), 8.41-8.35 (m,2H), 7.97-7.90 (m, 2H), 7.57 (s, 1H), 4.03 (s, 3H).

Synthesis of rac-methyl(3S,4S,5R)-8-chloro-5,10,10-trihydroxy-6-methoxy-3-phenyl-2-(4-(trifluoromethyl)phenyl)-2,3,4, 5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate (6)

To a 250 mL round bottom flask was added sequentially: a stir bar,7-chloro-3-hydroxy-5-methoxy-2-(4-(trifluoromethyl)phenyl)-4H-pyrano[3,2-c]pyridin-4-one(4, 317 mg, 0.850 mmol), methyl cinnamate (5, 1.38 g, 8.53 mmol),chloroform (15 mL), and trifluoroethanol (15 mL). The reaction mixturewas stirred vigorously and irradiated with 450 W UV light while beingcooled with a 0° C. cold bath for 3 h. The reaction mixture was dilutedwith 3% triethylamine in ethyl acetate (15 mL), concentrated on a rotaryevaporator with silica gel, and dried under high vacuum for 2 h. Theresidue was loaded into a loading column and purified via silica gelchromatography (0-5-100% EtOAc/hexanes) to afford impure rac-methyl(3S,4S,5R)-8-chloro-5,10,10-trihydroxy-6-methoxy-3-phenyl-2-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate(6) as an orange residue. Yield: 273 mg; MS (ESI) m/z 552.2 [M]⁺. Thismaterial was taken on to the next step without further purification.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-1-methoxy-8-oxo-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(7)

Sodium methoxide (25 wt. % in methanol) (0.34 mL, 1.49 mmol) was addedto a stirred solution of rac-methyl(3S,4S,5R)-8-chloro-5,10,10-trihydroxy-6-methoxy-3-phenyl-2-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate(6, 273 mg, 0.490 mmol) in methanol (10 mL) at room temperature underargon. The clear yellow solution changed to dark orange colored. Thereaction mixture was heated at 60° C. under a reflux condenser underargon for 40 min and then most of the solvent was removed on a rotaryevaporator. The residue was partitioned between saturated aqueousammonium chloride and ethyl acetate. The organics were washed withbrine, dried over magnesium sulfate, filtered, concentrated on a rotaryevaporator, and dried under high vacuum to afford impure rac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-1-methoxy-8-oxo-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(7) as a yellow residue. Yield: 240 mg; MS (ESI) m/z 534.1[M+1]⁺. Thismaterial was carried on without further purification.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(8)

To a stirred solution of rac-methyl(5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-1-methoxy-8-oxo-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(7, 240 mg, 0.450 mmol) in MeCN (9 mL) at room temperature was addedacetic acid (0.26 mL, 4.5 mmol) and then sodium triacetoxyborohydride(476 mg, 2.25 mmol). The resulting reaction mixture was stirredvigorously at room temperature for 40 min. Saturated aqueous ammoniumchloride (5 mL) was added slowly dropwise and the resulting mixture waspartitioned between water and ethyl acetate. The organics were washedwith saturated aqueous sodium bicarbonate and then brine, dried overmagnesium sulfate, filtered, concentrated on a rotary evaporator andpurified via silica gel chromatography (12-22% EtOAc/hexanes) to affordrac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(8) as a slightly yellow semi-solid. Yield: 101 mg, 22% over threesteps; MS (ESI) m/z 536.2[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.38 (d,J=8.6 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.07-7.01 (m, 2H), 6.99-6.93 (m,4H), 5.76 (s, 1H), 5.72 (d, J=5.8 Hz, 1H), 4.65 (t, J=5.3 Hz, 1H), 4.37(d, J=14.0 Hz, 1H), 4.16 (dd, J=14.0, 4.9 Hz, 1H), 3.84 (s, 3H), 3.58(s, 3H).

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (9)

To a stirred mixture (not all dissolved) of rac-methyl(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(8, 97.6 mg, 0.180 mmol) in methanol (4 mL) was added water (0.4 mL) andthen lithium hydroxide (43.6 mg, 1.82 mmol). The resulting yellowreaction mixture was stirred and heated at 50° C. under a refluxcondenser under argon for 3 h. The reaction mixture was cooled with a 0°C. cold bath and 1 N hydrochloric acid in water (1.82 mL, 1.82 mmol) wasadded with vigorous stirring. A few more drops of 1 N hydrochloric acidwas added to make the mixture slightly acidic. Most of the methanol wasremoved on a rotary evaporator. The residue was extracted three timeswith dichloromethane. The combined organics were washed with brine,dried over magnesium sulfate, filtered, concentrated on a rotaryevaporator and dried under high vacuum at 40° C. overnight to affordcruderac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (9) as a white solid with yellow impurity. Yield: 84.8 mg, 89%; MS(ESI) m/z 522.3[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(10)

HATU (64.9 mg, 0.171 mmol) was added to a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (9, 84.8 mg, 0.162 mmol) in N,N-dimethylformamide (1.5 mL) at roomtemperature. After 2 min N,N-diisopropylethylamine (0.04 mL, 0.24 mmol)was added. The resulting reaction mixture was capped and stirred at roomtemperature for 20 min. Dimethylamine (2 M solution in THF) (0.24 mL,0.49 mmol) was added and the reaction mixture was capped and stirred atroom temperature for 40 min. The reaction mixture was diluted with ethylacetate and diethyl ether, washed three times with water, once withbrine, dried over magnesium sulfate, filtered, concentrated on a rotaryevaporator, and purified via silica gel chromatography (20-100%EtOAc/hexanes) to affordrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(10) as a white foam-solid. Yield: 83.0 mg, 93%; MS (ESI) m/z549.2[M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6, 7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 144F)

Borane dimethyl sulfide complex (0.14 mL, 1.51 mmol) was added to astirred solution ofrac-(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-N,N-dimethyl-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(10, 83.0 mg, 0.150 mmol) in THF (3.5 mL) at room temperature under areflux condenser under argon. Some bubbling was observed. The reactionmixture was heated at 40° C. under a reflux condenser under argon for3.5 h. After cooling to room temperature, wet methanol (2.5 mL) wasadded dropwise slowly. The resulting clear colorless reaction mixturewas stirred vigorously and heated at 65° C. under a reflux condenserunder argon for 43 h. The reaction mixture was loaded onto a 2 g StrataX-C ion exchange column from Phenomenex. The column was washedsequentially with acetonitrile, methanol, and then 5% ammonium hydroxidein methanol/dichloromethane. Eluent containing the desired product wasconcentrated on a rotary evaporator. The residue was taken up in 50%acetonitrile in water (not all dissolved), sonicated for a few seconds,and then lyophilized to dryness to affordrac-(5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 144F) as a white solid. Yield: 74.0 mg, 91%; MS (ESI) m/z535.2[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.43-7.35 (m, 4H), 7.06 (dd,J=8.3, 6.3 Hz, 2H), 7.02-6.94 (m, 3H), 6.89 (s, 1H), 5.64 (s, 1H), 5.20(s, 1H), 4.46 (d, J=4.1 Hz, 1H), 3.84 (s, 3H), 3.75 (d, J=14.0 Hz, 1H),3.14 (ddt, J=13.9, 9.8, 3.7 Hz, 1H), 2.62-2.53 (m, 1H), 2.21 (s, 6H),1.97 (d, J=12.0 Hz, 1H).

Example 145(5aR,6S,7S,8R,8aS)-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 145F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(2)

Rac-1-((5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-5a-(4-chlorophenyl)-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)-N,N-dimethylmethanamine(1, 40.8 mg, 0.059 mmol), zinc powder (4.5 mg, 0.069 mmol), zinc cyanide(20.9 mg, 0.178 mmol), dppf (3.3 mg, 0.006 mmol), Pd₂dba₃ (2.7 mg, 0.003mmol), N,N-dimethylformamide (0.55 mL), and water (0.055 mL) werecombined in a 1 dram vial with a stirbar. The mixture was sparged withargon gas for 5 min and then sealed, stirred vigorously, and heated at100° C. with a block heater for 2.5 h. More of all the reagents wasadded (including water). The mixture was sparged with argon gas for 5min and then sealed, stirred vigorously, and heated at 110° C. with ablock heater for 5.5 h. After cooling to room temperature the reactionmixture was diluted with methanol, filtered, and purified viapreparatory HPLC (30-85% acetonitrile in water with 0.1% TFA). Fractionscontaining the desired product were combined and lyophilized to drynessto affordrac-(5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(2) as an off-white solid. Yield: 17.6 mg, 44%; MS (ESI) m/z678.4[M+1]⁺.

Synthesis of(5aR,6S,7S,8R,8aS)-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 145F)

Tetrabutylammonium fluoride (1 M in THF) (0.15 mL, 0.150 mmol) was addedto a stirred solution ofrac-(5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(2, 17.0 mg, 0.025 mmol) in THF (1.5 mL). The reaction mixture wassealed, stirred, and heated at 40° C. for 20 h. The solvent was removedon a rotary evaporator. The residue was taken up in DMSO and methanol,filtered, and purified via preparatory HPLC (15-40% acetonitrile inwater with 0.1% TFA). Fractions containing the desired product wereloaded onto a Strata X-C ion exchange column from Phenomenex. The columnwas washed sequentially with water, acetonitrile, methanol, and then 5%ammonium hydroxide in methanol/dichloromethane. Eluent containing thedesired product was concentrated on a rotary evaporator. The residue wastaken up in 50% acetonitrile in water (not all dissolved), sonicated fora few seconds, and then lyophilized to dryness to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrileas a white solid. Yield: 9.4 mg, 76%; The enantiomers were separated bychiral SFC [Chiralpak IG (4.6×250) mm, 5μ], CO₂/0.2% TEA in IPA 60/40(v/v). Peak 1 (Cpd. No. 145F, 2.60 g), [α]_(D) −71.6° (c 0.35, CHCl₃),R_(t)=1.978 min, ee: 99.48% MS (ESI) m/z 492.13[M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) 7.51 (s, 1H), 7.17 (d, J=8.60 Hz, 2H), 7.11-6.96 (m, 7H), 5.74(s, 1H), 5.29 (bs, 1H), 4.47 (d, J=3.6 Hz, 1H), 3.89 (s, 3H), 3.71 (d,J=14.04 Hz, 1H), 3.10 (t, J=12.0 Hz, 1H), 2.51 (bs, 1H), 2.20 (s, 6H),1.94 (t, J=12.52 Hz, 1H); Peak 2 (2.54 g), [α]_(D) +77.8° (c 0.30,CHCl₃), R_(t)=2.332 min, ee: 99.46% MS (ESI) m/z 492.15[M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) 7.51 (s, 1H), 7.17 (d, J=8.72 Hz, 2H), 7.11-6.96 (m,7H), 5.74 (s, 1H), 5.29 (bs, 1H), 4.47 (d, J=3.76 Hz, 1H), 3.89 (s, 3H),3.71 (d, J=13.96 Hz, 1H), 3.09 (t, J=10.7 Hz, 1H), 2.53 (bs, 1H), 2.19(s, 6H), 1.95-1.90 (m, 1H).

Example 146Rac-(5aR,6S,7S,8R,8aS)-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 146F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 146F)

Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 22.8 mg, 0.044 mmol), zinc powder (2.9 mg, 0.044 mmol), zinc cyanide(25.9 mg, 0.221 mmol), dppf (4.9 mg, 0.009 mmol), Pd₂dba₃ (4.0 mg, 0.004mmol), N,N-dimethylformamide (0.30 mL), and water (0.03 mL) werecombined in a microwave vial with a stirbar. The mixture was spargedwith argon gas for 5 min and then sealed, stirred, and microwaved at110° C. for 1 h. More of all of the reagents and water were added. Themixture was sparged with argon gas for 5 min and then sealed, stirred,and microwaved at 120° C. for 2 h. More of all of the reagents and waterwere added. The mixture was sparged with argon gas for 5 min and thensealed, stirred, and microwaved at 120° C. for 2 h. The reaction mixturewas diluted with DMSO and methanol, filtered, and purified viapreparatory HPLC (15-40% acetonitrile in water with 0.1% TFA). Fractionscontaining the desired product were loaded onto a Strata X-C ionexchange column from Phenomenex. The column was washed sequentially withwater, acetonitrile, methanol, and then 5% ammonium hydroxide inmethanol/dichloromethane. Eluent containing the desired product wasconcentrated on a rotary evaporator. The residue was taken up inwater/acetonitrile, sonicated for a few seconds, and lyophilized todryness to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 146F) as a white solid. Yield: 12.7 mg, 57%; MS (ESI) m/z508.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.55 (s, 1H), 7.37-7.21 (m,4H), 7.03 (dt, J=28.4, 7.6 Hz, 5H), 6.86 (t, J=55.9 Hz, 1H), 5.80 (s,1H), 5.34 (s, 1H), 4.53 (s, 1H), 3.89 (s, 3H), 3.74 (d, J=14.0 Hz, 1H),3.19 (m, 1H), 2.24 (s, 6H).

Example 147(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 147F)

Synthesis of(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 147F)

Rac-(5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 22.6 mg, 0.042 mmol), zinc powder (2.8 mg, 0.042 mmol), zinc cyanide(24.8 mg, 0.211 mmol), dppf (4.7 mg, 0.008 mmol), Pd₂dba₃ (3.9 mg, 0.004mmol), N,N-dimethylformamide (0.40 mL), and water (0.04 mL) werecombined in a microwave vial with a stirbar. The mixture was spargedwith argon gas for 5 min and then sealed, stirred, and microwaved at120° C. for 5 h. The reaction mixture was diluted with DMSO andmethanol, filtered, and purified via preparatory HPLC (15-43%acetonitrile in water with 0.1% TFA). Fractions containing the desiredproduct were loaded onto a Strata X-C ion exchange column fromPhenomenex. The column was washed sequentially with water, acetonitrile,methanol, and then 5% ammonium hydroxide in methanol/dichloromethane.Eluent containing the desired product was concentrated on a rotaryevaporator. The residue was taken up in water/acetonitrile, sonicatedfor a few seconds, and lyophilized to dryness to affordrac-(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrileas a white solid. Yield: 12.4 mg, 56%; The enantiomers were separated bychiral SFC [CHIRALPAK IG (4.6×250)mm, 5μ] in CO₂/MeOH/TEA (80:20:0.2).Peak 1 (650 mg), R_(t)=2.337 min, ee: 99.92%, [α]_(D) +74.10° (c 0.35,chloroform); MS (ESI) m/z 526.16 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 7.55(s, 1H), 7.42-7.39 (m, 4H), 7.08-6.96 (m, 5H), 5.82 (s, 1H), 5.33 (s,1H), 4.50 (d, J=3.2 Hz, 1H), 3.89 (s, 3H), 3.76 (d, J=14.12 Hz, 1H),3.16 (m, 1H), 2.55 (s, 2H), 2.21 (s, 6H), 1.95 (d, J=10.16 Hz, 1H).Peak-2 (Cpd. No. 147F, 650 mg), R_(t)=3.77 min, ee: 99.75%, [α]_(D)−80.4° (c 0.3, chloroform); MS (ESI) m/z 495.16[M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) 7.55 (s, 1H), 7.40 (s, 4H), 7.06-6.97 (m, 5H), 5.83 (s, 1H),5.33 (s, 1H), 4.51 (s, 1H), 3.89 (s, 3H), 3.76 (d, J=14.0 Hz, 1H), 3.17(m, 1H), 2.59-2.50 (m, 2H), 2.21 (s, 6H), 1.96 (bs, 1H).

Example 148Rac-(5aR,6S,7S,8R,8aS)-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 148F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6, 7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 148F)

Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 12.6 mg, 0.024 mmol), sodium bicarbonate (2.3 mg, 0.027 mmol), andmethanol (3 mL) were combined in a 10 mL conical flask with a stirbar. Acombination vacuum/hydrogen/argon manifold was attached and theatmosphere in the flask was removed and replaced with argon twice. 10%palladium on activated charcoal (5.2 mg, 0.005 mmol) was added and theatmosphere in the flask was removed and replaced with hydrogen twice.The reaction mixture was stirred vigorously at room temperature under ahydrogen balloon for 1.5 h. The reaction mixture was filtered through asyringe filter onto a 1 g Strata X-C ion exchange column fromPhenomenex. The column was washed sequentially with water, acetonitrile,methanol, and then 5% ammonium hydroxide in methanol/dichloromethane.Eluent containing the desired product was concentrated on a rotaryevaporator. The residue was taken up in water/acetonitrile, sonicatedfor a few seconds, and lyophilized to dryness to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 148F) as a white solid. Yield: 11.3 mg, 96%; MS (ESI) m/z483.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (d, J=5.7 Hz, 1H), 7.33(d, J=8.3 Hz, 2H), 7.27-7.21 (m, 2H), 7.09-7.01 (m, 2H), 7.01-6.94 (m,3H), 6.85 (t, J=56.0 Hz), 6.74 (d, J=5.7 Hz, 1H), 5.48 (s, 1H), 5.04 (s,1H), 4.51 (d, J=4.3 Hz, 1H), 3.85 (s, 3H), 3.69 (d, J=14.1 Hz, 1H), 3.17(m, 1H), 2.61 (m, 1H), 2.27 (s, 6H), 2.04 (m, 1H).

Example 149Rac-(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 149F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 149F)

Rac-(5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 12.5 mg, 0.023 mmol), sodium bicarbonate (2.2 mg, 0.026 mmol), andmethanol (3 mL) were combined in a 15 mL round bottom flask with astirbar. A combination vacuum/hydrogen/argon manifold was attached andthe atmosphere in the flask was removed and replaced with argon twice.10% palladium on activated charcoal (5.0 mg, 0.005 mmol) was added andthe atmosphere in the flask was removed and replaced with hydrogentwice. The reaction mixture was stirred vigorously at room temperatureunder a hydrogen balloon for 1.5 h. The reaction mixture was filteredthrough a syringe filter onto a 1 g Strata X-C ion exchange column fromPhenomenex. The column was washed sequentially with water, acetonitrile,methanol, and then 5% ammonium hydroxide in methanol/dichloromethane.Eluent containing the desired product was concentrated on a rotaryevaporator. The residue was taken up in water/acetonitrile, sonicatedfor a few seconds, and lyophilized to dryness to affordrac-(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 149F) as a white solid. Yield: 10.9 mg, 93%; MS (ESI) m/z501.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (d, J=5.7 Hz, 1H), 7.40(m, 4H), 7.10-6.94 (m, 5H), 6.76 (d, J=5.7 Hz, 1H), 5.56 (s, 1H), 5.10(s, 1H), 4.52 (s, 1H), 3.86 (s, 3H), 3.72 (d, J=14.0 Hz, 1H), 3.18 (m,1H), 2.28 (s, 6H).

Example 150Rac-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-3-(methylamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 150F)

Synthesis of rac-tert-butyl((5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-3-yl)(methyl)carbamate(3)

Rac-4-((5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(1, 30.9 mg, 0.046 mmol), Xantphos (5.3 mg, 0.009 mmol), Pd₂dba₃ (4.2mg, 0.005 mmol), cesium carbonate (74.2 mg, 0.228 mmol),tert-butyl-N-methylcarbamate (29.9 mg, 0.227 mmol), and 1,4-dioxane (0.7mL) were combined in a HPLC vial with a stirbar. The mixture was spargedwith argon gas for 5 min and then sealed, stirred vigorously, and heatedat 110° C. with a block heater for 2 h. The reaction mixture was loadeddirectly onto a silica gel loading column and purified via silica gelchromatography (5-50% EtOAc/hexanes) to afford impure rac-tert-butyl((5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-3-yl)(methyl)carbamate(3) as a yellow foam solid. Yield: 29.6 mg; MS (ESI) m/z 773.6 [M+1]⁺.This material was carried on to the next step without furtherpurification.

Synthesis ofrac-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-3-(methylamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 150F)

Tetrabutylammonium fluoride (1 M in THF) (0.57 mL, 0.57 mmol) was addedto a stirred solution of rac-tert-butyl((5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-3-yl)(methyl)carbamate(3, 29.6 mg, 0.038 mmol) in 1,4-dioxane (2 mL) in a sealable vial with astirbar. The reaction mixture was sealed, stirred, and heated at 60° C.for 19 h. The reaction mixture was concentrated, taken up in DMSO andmethanol, and purified via preparatory HPLC (15-50% acetonitrile inwater with 0.1% TFA). MS (ESI) m/z 587.5 [M+1]⁺. Fractions containingthe desired intermediate were combined and concentrated down to ˜15 mLon a rotary evaporator. Acetonitrile (5 mL) was added followed by TFA (1mL) (total volume ˜20 mL). The reaction mixture was stirred and heatedat 40° C. under a reflux condenser for 1 h 10 min and then concentratedon a rotary evaporator. The residue was taken up in DMSO/methanol andpurified via preparatory HPLC (15-28% acetonitrile in water with 0.1%TFA). Fractions containing the desired product were combined and loadedonto a Strata X-C ion exchange column from Phenomenex. The column waswashed sequentially with water, acetonitrile, methanol, and then 5%ammonium hydroxide in methanol/dichloromethane. Eluent containing thedesired product was concentrated on a rotary evaporator. The residue wastaken up in acetonitrile/water, sonicated for a few seconds, andlyophilized to dryness to affordrac-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-3-(methylamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 150F) as a white solid. Yield: 8.6 mg, 39% over three steps;MS (ESI) m/z 487.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.52-7.47 (m,2H), 7.37-7.32 (m, 2H), 7.07 (dd, J=8.0, 6.6 Hz, 2H), 7.03-6.93 (m, 3H),6.32 (m, 1H), 5.63 (s, 1H), 5.18 (s, 1H), 4.82 (s, 1H), 4.43 (s, 1H),3.78 (s, 3H), 3.67 (d, J=14.0 Hz, 1H), 3.16 (m, 1H), 2.75 (d, J=4.8 Hz,3H), 2.33 (br s, 6H).

Example 151(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 151F)

Synthesis ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(morpholino)methanone(2)

HATU (153 mg, 0.40 mmol) was added to a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 204 mg, 0.38 mmol) in N,N-dimethylformamide (3.5 mL) at roomtemperature under argon. After 2 min N,N-diisopropylethylamine (0.10 mL,0.57 mmol) was added. The resulting reaction mixture was stirred at roomtemperature under argon for 20 min. Morpholine (66.7 mg, 0.77 mmol) wasadded and the reaction mixture was stirred at room temperature underargon for 20 min. The reaction mixture was diluted with diethyl ether,washed three times with water, once with brine, dried over magnesiumsulfate, filtered, concentrated on a rotary evaporator, and purified viasilica gel chromatography (20-100% EtOAc/hexanes) to affordrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(morpholino)methanone(2) as a white foam-solid. Yield: 186 mg, 81%; MS (ESI) m/z 601.3, 603.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.24-7.19 (m, 2H), 7.08-7.01 (m,4H), 6.99-6.89 (m, 4H), 5.62 (s, 1H), 5.31 (d, J=5.8 Hz, 1H), 4.63 (t,J=5.5 Hz, 1H), 4.43 (d, J=13.3 Hz, 1H), 4.22 (dd, J=13.4, 5.2 Hz, 1H),3.90 (m, 1H), 3.84 (s, 3H), 3.82-3.55 (m, 4H), 3.46 (m, 2H).

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-7-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3)

Borane dimethyl sulfide complex (0.29 mL, 3.06 mmol) was added to astirred solution ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(morpholino)methanone(2, 184 mg, 0.310 mmol) in THF (5 mL) at room temperature under a refluxcondenser under argon. Some bubbling was observed. The reaction mixturewas heated at 40° C. under a reflux condenser under argon for 3 h 45min. After cooling to room temperature, wet methanol (5 mL) was addeddropwise slowly. The resulting clear colorless reaction mixture wasstirred vigorously and heated at 65° C. under a reflux condenser underargon for 40 h. The reaction mixture was loaded directly onto a five gStrata X-C ion exchange column from Phenomenex. The column was washedsequentially with water, acetonitrile, methanol, and then a mixture of5% ammonium hydroxide in dichloromethane/methanol. Eluent containing thedesired product was concentrated on a rotary evaporator and dried underhigh vacuum at 40° C. to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-7-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3) as a white solid. Yield: 163 mg, 91%; MS (ESI) m/z 587.4, 589.2; ¹HNMR (400 MHz, DMSO-d₆) δ 7.22 (d, J=8.6 Hz, 2H), 7.13-7.05 (m, 4H),7.04-6.94 (m, 3H), 6.86 (s, 1H), 5.56 (s, 1H), 5.09 (d, J=5.1 Hz, 1H),4.44 (t, J=4.4 Hz, 1H), 3.84 (s, 3H), 3.70 (d, J=14.1 Hz, 1H), 3.61 (m,4H), 3.16 (m, 1H), 2.61-2.53 (m, 2H), 2.31 (m, 2H), 2.03 (d, J=11.2 Hz,1H).

Synthesis of(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 151F)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-7-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3, 30.2 mg, 0.051 mmol), zinc cyanide (36.2 mg, 0.308 mmol), zincpowder (3.4 mg, 0.051 mmol), Pd₂dba₃ (4.7 mg, 0.005 mmol), dppf (5.7 mg,0.010 mmol), N,N-dimethylformamide (0.3 mL), and water (0.03 mL) werecombined in a 1 dram vial with a stirbar. The reaction mixture wasstirred at room temperature while being sparged with argon gas for 2min. The reaction mixture was sealed, stirred, and heated at 110° C.with a block heater for 2 h. The reaction mixture was diluted with DMSOand methanol, filtered, and purified via preparatory HPLC (15-38%acetonitrile in water with 0.1% TFA). Fractions containing the desiredproduct were loaded onto a Strata X-C ion exchange column fromPhenomenex. The column was washed sequentially with water, acetonitrile,methanol, and then 5% ammonium hydroxide in methanol/dichloromethane.Eluent containing the desired product was concentrated on a rotaryevaporator. The residue was taken up in acetonitrile/water, sonicatedfor a few seconds, and lyophilized to dryness to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrileas a white solid. Yield: 19.5 mg, 72%; The enantiomers were separated bychiral SFC [Lux Amylose-1 (4.6×250) mm, 5μ] in C02/MeOH/TEA(60:40:0.2).Peak 1 (Cpd. No. 151F, 373 mg), R_(t)=1.379 min, ee: 99.86%, [α]_(D)−69.0° (c 0.20, CHCl₃); MS (ESI) m/z 525.20[M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) 7.55 (s, 1H), 7.51 (d, J=8.36 Hz, 2H), 7.36 (d, J=8.32 Hz, 2H),7.09-7.06 (m, 2H), 7.00-6.98 (m, 3H), 5.85 (s, 1H), 5.28 (s, 1H), 4.50(s, 1H), 3.89 (s, 3H), 3.79 (d, J=14.0 Hz, 1H), 3.61 (bs, 4H), 3.25 (bs,1H), 2.57 (bs, 2H), 2.32 (bs, 2H), 2.07 (bs, 1H). Peak-2 (383 mg),R_(t)=2.578 min, ee: 99.90%, %, [α]_(D) +68.8° (c 0.25, CHCl₃); MS (ESI)m/z 525.20[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 7.55 (s, 1H), 7.51 (d, J=7.2Hz, 2H), 7.36 (d, J=7.16 Hz, 2H), 7.08-7.01 (m, 5H), 5.85 (s, 1H), 5.29(bs, 1H), 4.50 (s, 1H), 3.90 (s, 3H), 3.78 (d, J=14.0 Hz, 1H), 3.61 (bs,3H), 3.50 (s, 1H), 3.26 (s, 1H), 2.57 (bs, 2H), 2.32 (bs, 2H), 2.07 (bs,1H).

Example 152

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 152F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-1-methoxy-7-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(2)

Rac-tert-Butyldimethylsilyl trifluoromethanesulfonate (0.16 mL, 0.67mmol) was added to a stirred mixture (not all dissolved) of(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-7-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 132 mg, 0.225 mmol) and 2,6-lutidine (0.16 mL, 1.35 mmol) in DCE (2mL) at room temperature under argon. (All solids dissolved) The reactionmixture was sealed and stirred at room temperature for 11 h. Thereaction mixture was loaded directly onto a silica gel loading columnand purified via silica gel chromatography (5-30% EtOAc/hexanes) toaffordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-1-methoxy-7-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(2) as a white foam-solid. Yield: 151 mg, 96%; MS (ESI) m/z 701.3, 703.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.20-7.14 (m, 2H), 7.13-6.96 (m,7H), 6.89 (s, 1H), 5.87 (s, 1H), 4.48 (d, J=2.8 Hz, 1H), 4.02 (d, J=13.8Hz, 1H), 3.79 (s, 3H), 3.68-3.58 (m, 4H), 3.49-3.34 (m, 1H), 2.63-2.54(m, 1H), 2.31-2.25 (m, 2H), 2.08 (dd, J=12.2, 2.8 Hz, 1H), 0.69 (s, 9H),0.13 (s, 3H), −0.30 (s, 3H).

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-1-methoxy-7-(morpholinomethyl)-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine(3)

Trimethylsilyl trifluoromethanesulfonate (0.06 mL, 0.32 mmol) was addedto a stirred mixture ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-1-methoxy-7-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(2, 149 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.64mmol) in DCE (2 mL) at room temperature under argon. The reactionmixture was heated at 40° C. under a reflux condenser under argon for1.5 h. More N,N-diisopropylethylamine (0.11 mL, 0.64 mmol) was addedfollowed by trimethylsilyl trifluoromethanesulfonate (0.06 mL, 0.32mmol). The reaction mixture was heated at 40° C. under a refluxcondenser under argon for 1 h. The reaction mixture was partitionedbetween dichloromethane and saturated aqueous sodium bicarbonate. Thewater layer was extracted with dichloromethane. The combined organicswere concentrated to dryness and purified via silica gel chromatography(1-20% EtOAc/hexanes) to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-1-methoxy-7-(morpholinomethyl)-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine(3) as a white solid. Yield: 155 mg, 94%; MS (ESI) m/z 773.3, 775.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.24-7.18 (m, 2H), 7.15-6.94 (m,4H), 7.05-6.93 (m, 4H), 4.56 (d, J=3.4 Hz, 1H), 3.98 (d, J=13.0 Hz, 1H),3.66-3.54 (m, 4H), 3.30-3.23 (m, 1H), 2.58-2.52 (m, 1H), 2.35-2.29 (m,1H), 2.18 (dd, J=12.5, 3.5 Hz, 1H), 0.72 (s, 9H), 0.14 (s, 3H), −0.13(s, 9H), −0.22 (s, 3H).

Synthesis ofrac-4-((5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-1-methoxy-7-(morpholinomethyl)-6-phenyl-8a-((trimethylsilyl)oxy)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(4)

p-Toluenesulfonyl cyanide from Aldrich (248835) was recrystallized fromtoluene/hexanes, dissolved in THF, and dried over 4 Angstrom molecularsieves for 3 hours prior to use.Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-1-methoxy-7-(morpholinomethyl)-6-phenyl-8a-((trimethylsilyl)oxy)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine(3, 151 mg, 0.195 mmol) was dissolved in THF (2 mL) with stirring underargon. The resulting colorless solution was cooled to −78° C. with a dryice/acetone bath for 10 min. n-Butyllithium (2.5 M in hexane) (0.086 mL,0.215 mmol) was added slowly. The slightly yellow reaction mixture wasstirred at −78° C. under argon for 30 min. p-Toluenesulfonyl cyanide (2M in THF) (0.14 mL, 0.27 mmol) was added and the resulting mixture wasstirred at −78° C. under argon for 30 min. Saturated aqueous ammoniumchloride (1 mL) was added. After warming to room temperature, theresulting mixture was partitioned between water and ethyl acetate. Theorganics were washed with brine, dried over magnesium sulfate, filtered,concentrated on a rotary evaporator, and purified via preparatory HPLC(35-82% acetonitrile in water with 0.1% TFA). Fractions containing thedesired product were combined, neutralized with saturated aqueous sodiumbicarbonate, and the acetonitrile was removed on a rotary evaporator.The residue was extracted twice with dichloromethane. The organics weredried over Na₂SO₄, filtered, concentrated on a rotary evaporator, anddried under high vacuum to affordrac-4-((5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-1-methoxy-7-(morpholinomethyl)-6-phenyl-8a-((trimethylsilyl)oxy)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(4) as a slightly yellow foam solid. Yield: 52.8 mg, 38%; MS (ESI) m/z720.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.53-7.48 (m, 2H), 7.24-7.19(m, 2H), 7.15-7.08 (m, 4H), 7.03-6.99 (m, 2H), 4.57 (d, J=3.3 Hz, 1H),4.03 (d, J=13.1 Hz, 1H), 3.83 (s, 3H), 3.67-3.55 (m, 4H), 3.38-3.33 (m,1H), 2.58-2.52 (m, 1H), 2.37-2.32 (m, 2H), 2.20 (dd, J=12.4, 3.4 Hz,1H), 0.72 (s, 9H), 0.15 (s, 3H), −0.11 (s, 9H), −0.23 (s, 3H).

Synthesis ofrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 152F)

Tetrabutylammonium fluoride (1 M in THF) (0.24 mL, 0.24 mmol) was addedto a stirred solution ofrac-4-((5aR,6S,7S,8R,8aS)-8-((tert-butyldimethylsilyl)oxy)-3-chloro-1-methoxy-7-(morpholinomethyl)-6-phenyl-8a-((trimethylsilyl)oxy)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(4, 28.9 mg, 0.040 mmol) in THF (2 mL). The reaction mixture was stirredand heated at 40° C. under a reflux condenser under argon for 14 h. Thesolvent was removed on a rotary evaporator. The residue was taken up inDMSO and methanol, filtered, and purified via preparatory HPLC (15-38%acetonitrile in water with 0.1% TFA). Fractions containing the desiredproduct were loaded onto a Strata X-C ion exchange column fromPhenomenex. The column was washed sequentially with water, acetonitrile,methanol, and then 10% ammonium hydroxide in methanol/dichloromethane.Eluent containing the desired product was concentrated on a rotaryevaporator. The residue was taken up in 50% acetonitrile in water,sonicated for a few seconds, and lyophilized to dryness to affordrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 152F) as a white solid. Yield: 15.5 mg, 72%; MS (ESI) m/z534.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.53-7.47 (m, 2H), 7.38-7.33(m, 2H), 7.10-7.04 (m, 2H), 7.01-6.97 (m, 3H), 6.89 (s, 1H), 5.66 (s,1H), 5.15 (d, J=5.2 Hz, 1H), 4.46 (t, J=4.3 Hz, 1H), 3.85 (s, 3H), 3.77(d, J=14.0 Hz, 1H), 3.68-3.55 (m, 4H), 3.22 (ddt, J=14.0, 10.2, 3.6 Hz,1H), 2.62-2.56 (m, 2H), 2.34-2.29 (m, 2H), 2.09-2.03 (m, 1H).

Example 153Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoropyrrolidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 153F)

Synthesis ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3,3-difluoropyrrolidin-1-yl)methanone(3)

HATU (30.7 mg, 0.081 mmol) was added to a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 40.9 mg, 0.077 mmol) in N,N-dimethylformamide (0.70 mL) at roomtemperature under argon. After 2 min N,N-diisopropylethylamine (0.033mL, 0.192 mmol) was added. The resulting reaction mixture was stirred atroom temperature under argon for 20 min. 3,3-Difluoropyrrolidinehydrochloride (2, 22.1 mg, 0.154 mmol) was added and the reactionmixture was stirred at room temperature under argon for 40 min. Thereaction mixture was diluted with ethyl acetate, washed three times withbrine, dried over magnesium sulfate, filtered, concentrated on a rotaryevaporator, and purified via silica gel chromatography (10-100%EtOAc/hexanes) to affordrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3,3-difluoropyrrolidin-1-yl)methanone(3) as a white solid. Yield: 47.7 mg, 99.9%; MS (ESI) m/z 621.1, 623.1[M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-difluoropyrrolidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4)

Borane dimethyl sulfide complex (0.109 mL, 1.15 mmol) was added to astirred solution ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3,3-difluoropyrrolidin-1-yl)methanone(3, 47.7 mg, 0.077 mmol) in THF (1 mL) at room temperature under areflux condenser under argon. Some bubbling was observed. The reactionmixture was heated at 40° C. under a reflux condenser under argon for 7h. After cooling to room temperature, wet methanol (1 mL) was addeddropwise slowly. The resulting clear colorless reaction mixture wasstirred vigorously and heated at 65° C. under a reflux condenser underargon for 10 h. The reaction mixture was loaded directly onto a StrataX-C ion exchange column from Phenomenex. The column was washedsequentially with water, acetonitrile, methanol, and then a mixture of5% ammonium hydroxide in dichloromethane/methanol. Eluent containing thedesired product was concentrated on a rotary evaporator and dried underhigh vacuum at 40° C. to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-difluoropyrrolidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4) as a white solid. Yield: 37.5 mg, 80%; MS (ESI) m/z 607.1, 609.2[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.25-7.20 (m, 2H), 7.14-7.06 (m,4H), 7.03-6.96 (m, 3H), 6.86 (s, 1H), 5.59 (s, 1H), 5.16 (d, J=5.3 Hz,1H), 4.43 (t, J=4.7 Hz, 1H), 3.84 (s, 3H), 3.70 (d, J=14.1 Hz, 1H),3.19-3.05 (m, 2H), 2.92-2.65 (m, 4H), 2.31-2.18 (m, 2H), 2.13 (dd,J=11.9, 2.9 Hz, 1H).

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoropyrrolidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 153F)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-difluoropyrrolidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4, 35.2 mg, 0.058 mmol), zinc cyanide (40.8 mg, 0.347 mmol), zincpowder (3.8 mg, 0.058 mmol), Pd₂dba₃ (5.3 mg, 0.006 mmol), dppf (6.44mg, 0.012 mmol), N,N-dimethylformamide (0.30 mL), and water (0.03 mL)were combined in a 1 dram vial with a stirbar. The reaction mixture wasstirred at room temperature while being sparged with argon gas for 2min. The reaction mixture was sealed, stirred, and heated at 110° C.with a block heater for 2 h. The reaction mixture was diluted with DMSOand methanol, filtered, and purified via preparatory HPLC (15-40%acetonitrile in water with 0.1% TFA). Fractions containing the desiredproduct were loaded onto a Strata X-C ion exchange column fromPhenomenex. The column was washed sequentially with water, acetonitrile,methanol, and then 5% ammonium hydroxide in methanol/dichloromethane.Eluent containing the desired product was concentrated on a rotaryevaporator. The residue was taken up in acetonitrile/water, sonicatedfor a few seconds, and lyophilized to dryness to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoropyrrolidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 153F) as a white solid. Yield: 20.8 mg, 66%; MS (ESI) m/z545.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.55 (s, 1H), 7.53-7.49 (m,2H), 7.40-7.35 (m, 2H), 7.11-7.05 (m, 2H), 7.03-6.97 (m, 3H), 5.88 (s,1H), 5.36 (d, J=5.5 Hz, 1H), 4.50 (dd, J=5.3, 4.1 Hz, 1H), 3.90 (s, 3H),3.77 (d, J=14.1 Hz, 1H), 3.22-3.12 (m, 2H), 2.91-2.68 (m, 4H), 2.30-2.19(m, 2H), 2.15 (dd, J=11.9, 2.9 Hz, 1H).

Example 154Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 154F)

Synthesis ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3,3-difluoropiperidin-1-yl)methanone(3)

HATU (29.5 mg, 0.077 mmol) was added to a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 39.3 mg, 0.074 mmol) in N,N-dimethylformamide (0.70 mL) at roomtemperature under argon. After 2 min N,N-diisopropylethylamine (0.032mL, 0.184 mmol) was added. The resulting reaction mixture was stirred atroom temperature under argon for 20 min. 3,3-Difluoropiperidinehydrochloride (2, 23.3 mg, 0.148 mmol) was added and the reactionmixture was stirred at room temperature under argon for 40 min. Thereaction mixture was diluted with ethyl acetate, washed three times withbrine, dried over magnesium sulfate, filtered, concentrated on a rotaryevaporator, and purified via silica gel chromatography (10-100%EtOAc/hexanes) to affordrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3,3-difluoropiperidin-1-yl)methanone(3) as a white solid. Yield: 42.6 mg, 91%; MS (ESI) m/z 635.3, 637.1[M+1]+.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-difluoropiperidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (4)

Borane dimethyl sulfide complex (0.095 mL, 1.00 mmol) was added to astirred solution ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3,3-difluoropiperidin-1-yl)methanone(3, 42.6 mg, 0.067 mmol) in THF (1 mL) at room temperature under areflux condenser under argon. Some bubbling was observed. The reactionmixture was heated at 40° C. under a reflux condenser under argon for 7h. After cooling to room temperature, wet methanol (1 mL) was addeddropwise slowly. The resulting clear colorless reaction mixture wasstirred vigorously and heated at 65° C. under a reflux condenser underargon for 10 h. The reaction mixture was loaded directly onto a StrataX-C ion exchange column from Phenomenex. The column was washedsequentially with water, acetonitrile, methanol, and then a mixture of5% ammonium hydroxide in dichloromethane/methanol. Eluent containing thedesired product was concentrated on a rotary evaporator and dried underhigh vacuum at 40° C. to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-difluoropiperidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4) as a white solid. Yield: 37.5 mg, 90%; MS (ESI) m/z 621.1, 623.2[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.24-7.21 (m, 2H), 7.15-7.05 (m,4H), 7.02-6.98 (m, 3H), 6.86 (s, 1H), 5.58 (s, 1H), 5.08 (d, J=5.2 Hz,1H), 4.41 (t, J=4.6 Hz, 1H), 3.85 (s, 3H), 3.71 (d, J=14.0 Hz, 1H),3.23-3.13 (m, 3H), 2.92 (q, J=11.4 Hz, 1H), 2.70-2.54 (m, 2H), 2.43-2.35(m, 1H), 2.14 (dd, J=12.7, 2.9 Hz, 1H), 1.93-1.82 (m, 2H), 1.72-1.62 (m,2H).

Synthesis of rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 154F)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-difluoropiperidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4, 35.6 mg, 0.057 mmol), zinc cyanide (40.3 mg, 0.343 mmol), zincpowder (3.7 mg, 0.057 mmol), Pd₂dba₃ (5.2 mg, 0.006 mmol), dppf (6.4 mg,0.011 mmol), N,N-dimethylformamide (0.30 mL), and water (0.03 mL) werecombined in a 1 dram vial with a stirbar. The reaction mixture wasstirred at room temperature while being sparged with argon gas for 2min. The reaction mixture was sealed, stirred, and heated at 110° C.with a block heater for 2 h. The reaction mixture was diluted with DMSOand methanol, filtered, and purified via preparatory HPLC (15-42%acetonitrile in water with 0.1% TFA). Fractions containing the desiredproduct were loaded onto a Strata X-C ion exchange column fromPhenomenex. The column was washed sequentially with water, acetonitrile,methanol, and then 5% ammonium hydroxide in methanol/dichloromethane.Eluent containing the desired product was concentrated on a rotaryevaporator. The residue was taken up in acetonitrile/water, sonicatedfor a few seconds, and lyophilized to dryness to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 154F) as a white solid. Yield: 21.9 mg, 68%; MS (ESI) m/z559.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.55 (s, 1H), 7.53-7.48 (m,2H), 7.41-7.36 (m, 2H), 7.11-7.05 (m, 2H), 7.04-6.97 (m, 3H), 5.86 (s,1H), 5.27 (d, J=5.3 Hz, 1H), 4.50-4.45 (m, 1H), 3.90 (s, 3H), 3.78 (d,J=14.0 Hz, 1H), 3.29-3.22 (m, 1H), 2.96 (q, J=11.4 Hz, 1H), 2.71-2.54(m, 3H), 2.43-2.37 (m, 1H), 2.15 (dd, J=12.6, 2.9 Hz, 1H), 1.93-1.82 (m,2H), 1.72-1.63 (m, 2H).

Example 155Rac-(5aR,6S,7S,8R,8aS)-7-((tert-butylamino)methyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 155F)

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-N-(tert-butyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(3)

HATU (46.4 mg, 0.122 mmol) was added to a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 61.9 mg, 0.116 mmol) in N,N-dimethylformamide (1 mL) at roomtemperature. After 2 min N,N-diisopropylethylamine (0.030 mL, 0.174mmol) was added. The resulting reaction mixture was capped and stirredat room temperature for 20 min. 2-methylpropan-2-amine (2, 0.24 mL, 2.32mmol) was added and the reaction mixture was capped and stirred at roomtemperature for 1 h. The reaction mixture was diluted with ethylacetate, washed three times with brine, dried over magnesium sulfate,filtered, concentrated on a rotary evaporator, and purified via silicagel chromatography (20-60% EtOAc/hexanes) to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-N-(tert-butyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(3) as a white solid. Yield: 61.7 mg, 90%; MS (ESI) m/z 587.3, 589.1[M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((tert-butylamino)methyl)-3-chloro-1-methoxy-6-phenyl-5a,6,7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (4)

Borane dimethyl sulfide complex (0.049 mL, 0.512 mmol) was added to astirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-N-(tert-butyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(3, 30.1 mg, 0.051 mmol) in THF (1.5 mL) at room temperature under areflux condenser under argon. Some bubbling was observed. The reactionmixture was heated at 40° C. under a reflux condenser under argon for 6h. After cooling to room temperature, wet methanol (1 mL) was addeddropwise slowly. The resulting clear colorless reaction mixture wasstirred vigorously and heated at 65° C. under a reflux condenser underargon for 9.5 h. The reaction mixture was loaded directly onto a StrataX-C ion exchange column from Phenomenex. The column was washedsequentially with water, acetonitrile, methanol, and then a mixture of5% ammonium hydroxide in dichloromethane/methanol. Eluent containing thedesired product was concentrated on a rotary evaporator and dried underhigh vacuum at 40° C. to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((tert-butylamino)methyl)-3-chloro-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4) as a white solid. Yield: 23.7 mg, 81%; MS (ESI) m/z 573.2, 575.1[M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-7-((tert-butylamino)methyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 155F)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((tert-butylamino)methyl)-3-chloro-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4, 20.8 mg, 0.036 mmol), zinc cyanide (25.5 mg, 0.217 mmol), zincpowder (2.4 mg, 0.036 mmol), Pd₂dba₃ (3.3 mg, 0.004 mmol), dppf (4.0 mg,0.007 mmol), N,N-dimethylformamide (0.30 mL), and water (0.03 mL) werecombined in a 1 dram vial with a stirbar. The reaction mixture wasstirred at room temperature while being sparged with argon gas for 2min. The reaction mixture was sealed, stirred, and heated at 110° C.with a block heater for 2 h. The reaction mixture was diluted with DMSOand methanol, filtered, and purified via preparatory HPLC (15-43%acetonitrile in water with 0.1% TFA). Fractions containing the desiredproduct were loaded onto a Strata X-C ion exchange column fromPhenomenex. The column was washed sequentially with water, acetonitrile,methanol, and then 5% ammonium hydroxide in methanol/dichloromethane.Eluent containing the desired product was concentrated on a rotaryevaporator. The residue was taken up in acetonitrile/water, sonicatedfor a few seconds, and lyophilized to dryness to affordrac-(5aR,6S,7S,8R,8aS)-7-((tert-butylamino)methyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 155F) as a white solid. Yield: 12.6 mg, 68%; MS (ESI) m/z511.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.56 (s, 1H), 7.55-7.49 (m,2H), 7.37-7.30 (m, 2H), 7.12-7.05 (m, 2H), 7.04-6.95 (m, 3H), 5.88 (s,1H), 5.78 (s, 1H), 4.55 (d, J=4.3 Hz, 1H), 3.90 (s, 3H), 3.85 (d, J=14.3Hz, 1H), 3.09-3.02 (m, 1H), 2.63 (d, J=9.2 Hz, 1H), 2.58-2.53 (m, 1H),0.96 (s, 9H).

Example 156Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((4-fluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 156aF)Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((4-fluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 156bF)Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((4-fluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 156cF)

Synthesis ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(4-fluoropiperidin-1-yl)methanone(3)

HATU (75.2 mg, 0.198 mmol) was added to a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 100.4 mg, 0.188 mmol) in N,N-dimethylformamide (1.5 mL) at roomtemperature under argon. After 2 min N,N-diisopropylethylamine (0.082mL, 0.471 mmol) was added. The resulting reaction mixture was stirred atroom temperature under argon for 20 min. 4-fluoropiperidinehydrochloride (2, 52.6 mg, 0.377 mmol) was added and the reactionmixture was stirred at room temperature under argon for 1 h. Thereaction mixture was diluted with ethyl acetate, washed three times withbrine, dried over magnesium sulfate, filtered, concentrated on a rotaryevaporator, and purified via silica gel chromatography (10-100%EtOAc/hexanes) to affordrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(4-fluoropiperidin-1-yl)methanone(3) as a white foam-solid. Yield: 107.6 mg, 92%; MS (ESI) m/z 617.3,619.3 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((4-fluoropiperidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4)

Borane dimethyl sulfide complex (0.165 mL, 1.74 mmol) was added to astirred solution ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(4-fluoropiperidin-1-yl)methanone(3, 107.6 mg, 0.174 mmol) in THF (2.5 mL) at room temperature under areflux condenser under argon. Some bubbling was observed. The reactionmixture was heated at 40° C. under a reflux condenser under argon for11.5 h. After cooling to room temperature, wet methanol (2 mL) was addeddropwise slowly. The resulting clear colorless reaction mixture wasstirred vigorously and heated at 65° C. under a reflux condenser underargon for 3 h 45 min. The reaction mixture was loaded directly onto aStrata X-C ion exchange column from Phenomenex. The column was washedsequentially with water, acetonitrile, methanol, and then a mixture of5% ammonium hydroxide in dichloromethane/methanol. Eluent containing thedesired product was concentrated on a rotary evaporator and dried underhigh vacuum at 40° C. to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((4-fluoropiperidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4) as a white solid. Yield: 102.4 mg, 97%; MS (ESI) m/z 603.4, 605.2[M+1]+.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((4-fluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 156aF)Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((4-fluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 156bF)Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((4-fluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 156cF)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((4-fluoropiperidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4, 25.1 mg, 0.042 mmol), zinc cyanide (24.4 mg, 0.208 mmol), zincpowder (0.3 mg, 0.004 mmol, Pd₂dba₃ (3.8 mg, 0.004 mmol), dppf (4.6 mg,0.008 mmol), N,N-dimethylformamide (0.60 mL), and water (0.06 mL) werecombined in a 1 dram vial with a stirbar. The reaction mixture wasstirred at room temperature while being sparged with argon gas for 2min. The reaction mixture was sealed, stirred, and heated at 110° C.with a block heater for 22 min. The reaction mixture was diluted withDMSO and methanol, filtered, and purified via preparatory HPLC (15-44%acetonitrile in water with 0.1% TFA). Fractions containing the desiredproduct were loaded onto a Strata X-C ion exchange column fromPhenomenex. The column was washed sequentially with water, acetonitrile,methanol, and then 5% ammonium hydroxide in methanol/dichloromethane.Eluent containing the desired product was concentrated on a rotaryevaporator. The residue was taken up in acetonitrile/water, sonicatedfor a few seconds, and lyophilized to dryness to afford the desiredproduct as a white solid.

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((4-fluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 156aF): Yield: 2.6 mg, 11%; MS (ESI) m/z 594.2, 596.2 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 7.52 (s, 1H), 7.25-7.22 (m, 2H), 7.14-7.05(m, 4H), 7.04-6.96 (m, 3H), 5.74 (s, 1H), 5.21 (s, 1H), 4.76-4.58 (m,1H), 4.47 (d, J=4.0 Hz, 1H), 3.89 (s, 3H), 3.71 (d, J=14.1 Hz, 1H),3.20-3.12 (m, 1H), 2.80-2.71 (m, 1H), 2.57 (dd, J=12.7, 10.2 Hz, 2H),2.48-2.38 (m, 1H), 2.30-2.17 (m, 1H), 2.04 (dd, J=12.6, 3.1 Hz, 2H),1.99-1.60 (m, 4H).

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((4-fluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 156bF): Yield: 5.7 mg, 25%; MS (ESI) m/z 550.3 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 7.53-7.47 (m, 2H), 7.38-7.33 (m, 2H), 7.10-7.04 (m,2H), 7.02-6.96 (m, 3H), 6.89 (s, 1H), 5.67 (s, 1H), 5.16 (s, 1H), 4.67(ddt, J=49.0, 7.3, 3.7 Hz, 1H), 4.44 (d, J=4.1 Hz, 1H), 3.84 (s, 3H),3.76 (d, J=14.0 Hz, 1H), 3.25-3.17 (m, 1H), 2.81-2.70 (m, 1H), 2.59 (dd,J=12.6, 10.1 Hz, 1H), 2.26-2.19 (m, 1H), 2.10-2.03 (m, 1H), 1.98-1.62(m, 4H).

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((4-fluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 156cF): Yield: 5.6 mg, 25%; MS (ESI) m/z 541.3 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 7.55 (s, 1H), 7.53-7.49 (m, 2H), 7.39-7.34 (m, 2H),7.10-7.04 (m, 2H), 7.02-6.97 (m, 3H), 5.85 (s, 1H), 5.28 (s, 1H),4.76-4.58 (m, 1H), 4.49 (d, J=4.0 Hz, 1H), 3.90 (s, 3H), 3.77 (d, J=14.0Hz, 1H), 3.27-3.17 (m, 1H), 2.81-2.70 (m, 1H), 2.59 (dd, J=12.6, 10.1Hz, 1H), 2.25-2.19 (m, 1H), 2.11-2.03 (m, 1H), 1.98-1.65 (m, 4H).

Example 157Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 157aF)Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 157bF)Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 157cF)

Synthesis ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(4,4-difluoropiperidin-1-yl)methanone(3)

HATU (74.9 mg, 0.197 mmol) was added to a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 99.9 mg, 0.188 mmol) in N,N-dimethylformamide (1.5 mL) at roomtemperature. After 2 min N,N-diisopropylethylamine (0.049 mL, 0.281mmol) was added. The resulting reaction mixture was capped and stirredat room temperature for 20 min. 4,4-Difluoropiperidine (2, 45.4 mg,0.375 mmol) was added and the reaction mixture was capped and stirred atroom temperature for 40 min. The reaction mixture was diluted with ethylacetate, washed once with water, twice with brine, dried over magnesiumsulfate, filtered, concentrated on a rotary evaporator, and purified viasilica gel chromatography (10-80% EtOAc/hexanes) to affordrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(4,4-difluoropiperidin-1-yl)methanone(3) as a white solid. Yield: 113.7 mg, 95%; MS (ESI) m/z 635.3, 637.2[M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((4,4-difluoropiperidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4)

Borane dimethyl sulfide complex (0.254 mL, 2.68 mmol) was added to astirred solution ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(4,4-difluoropiperidin-1-yl)methanone(3, 113.7 mg, 0.179 mmol) in THF (3 mL) at room temperature under areflux condenser under argon. Some bubbling was observed. The reactionmixture was heated at 40° C. under a reflux condenser under argon for 17h. After cooling to room temperature, wet methanol (2 mL) was addeddropwise slowly. The resulting clear colorless reaction mixture wasstirred vigorously and heated at 65° C. under a reflux condenser underargon for 2.5 h. The reaction mixture was loaded directly onto a StrataX-C ion exchange column from Phenomenex. The column was washedsequentially with water, acetonitrile, methanol, and then a mixture of5% ammonium hydroxide in dichloromethane/methanol. Eluent containing thedesired product was concentrated on a rotary evaporator and dried underhigh vacuum at 40° C. to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((4,4-difluoropiperidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4) as a white solid. Yield: 102.6 mg, 92%; MS (ESI) m/z 621.2, 623.2[M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 157aF)Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 157bF)Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 157cF)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((4,4-difluoropiperidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4, 39.9 mg, 0.064 mmol), zinc cyanide (37.7 mg, 0.321 mmol), zincpowder (0.4 mg, 0.006 mmol), Pd₂dba₃ (5.9 mg, 0.006 mmol), dppf (7.1 mg,0.013 mmol), N,N-dimethylformamide (0.90 mL), and water (0.09 mL) werecombined in a 1 dram vial with a stirbar. The reaction mixture wasstirred at room temperature while being sparged with argon gas for 2min. The reaction mixture was sealed, stirred, and heated at 110° C.with a block heater for 25 min. The reaction mixture was diluted withDMSO and methanol, filtered, and purified via preparatory HPLC (15-46%acetonitrile in water with 0.1% TFA). Fractions containing the desiredproduct were loaded onto a Strata X-C ion exchange column fromPhenomenex. The column was washed sequentially with water, acetonitrile,methanol, and then 5% ammonium hydroxide in methanol/dichloromethane.Eluent containing the desired product was concentrated on a rotaryevaporator. The residue was taken up in acetonitrile/water, sonicatedfor a few seconds, and lyophilized to dryness to afford the desiredproduct as a white solid.Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 157aF): Yield: 3.2 mg, 8%; MS (ESI) m/z 612.2, 614.1 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 7.52 (s, 1H), 7.25-7.22 (m, 2H), 7.15-7.06(m, 4H), 7.04-6.96 (m, 3H), 5.75 (s, 1H), 5.19 (s, 1H), 4.49 (s, 1H),3.90 (s, 3H), 3.70 (d, J=14.1 Hz, 1H), 3.21-3.13 (m, 1H), 2.74-2.58 (m,3H), 2.47-2.39 (m, 2H), 2.10 (dd, J=12.5, 3.1 Hz, 1H), 2.05-1.90 (m,4H).

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 157bF): Yield: 8.2 mg, 23%; MS (ESI) m/z 568.3 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 7.53-7.48 (m, 2H), 7.39-7.34 (m, 2H), 7.11-7.04 (m,2H), 7.02-6.96 (m, 3H), 6.90 (s, 1H), 5.67 (s, 1H), 5.14 (d, J=5.2 Hz,1H), 4.46 (t, J=4.6 Hz, 1H), 3.85 (s, 3H), 3.76 (d, J=14.0 Hz, 1H),3.26-3.17 (m, 1H), 2.76-2.60 (m, 3H), 2.48-2.42 (m, 2H), 2.13 (dd,J=12.7, 3.1 Hz, 1H), 2.04-1.91 (m, 4H).

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 157cF): Yield: 6.7 mg, 19%; MS (ESI) m/z 559.3 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 7.55 (s, 1H), 7.54-7.49 (m, 2H), 7.40-7.35 (m, 2H),7.10-7.04 (m, 2H), 7.03-6.97 (m, 3H), 5.85 (s, 1H), 5.26 (d, J=5.4 Hz,1H), 4.50 (t, J=4.6 Hz, 1H, 3.90 (s, 3H), 3.77 (d, J=14.0 Hz, 1H),3.28-3.20 (m, 1H), 2.76-2.59 (m, 3H), 2.47-2.41 (m, 2H), 2.13 (dd,J=12.5, 3.1 Hz, 1H), 2.04-1.91 (m, 4H).

Example 158Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 158aF)Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 158bF)Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 158cF)

Synthesis ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(pyrrolidin-1-yl)methanone(3)

H ATU (75.2 mg, 0.198 mmol) was added to a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 100.4 mg, 0.188 mmol) in N,N-dimethylformamide (1.5 mL) at roomtemperature under argon. After 2 min N,N-diisopropylethylamine (0.082mL, 0.471 mmol) was added. The resulting reaction mixture was stirred atroom temperature under argon for 20 min. Pyrrolidine (2, 26.8 mg, 0.377mmol) was added and the reaction mixture was stirred at room temperatureunder argon for 25 min. The reaction mixture was diluted with ethylacetate, washed three times with brine, dried over magnesium sulfate,filtered, concentrated on a rotary evaporator, and purified via silicagel chromatography (10-100% EtOAc/hexanes) to affordrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(pyrrolidin-1-yl)methanone(3) as a white foam-solid. Yield: 110 mg, 99.9%; MS (ESI) m/z 585.2,587.3 [M+1]+.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-5a,6, 7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (4)

Borane dimethyl sulfide complex (0.178 mL, 1.88 mmol) was added to astirred solution ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(pyrrolidin-1-yl)methanone(3, 110 mg, 0.188 mmol) in THF (3 mL) at room temperature under a refluxcondenser under argon. Some bubbling was observed. The reaction mixturewas heated at 40° C. under a reflux condenser under argon for 8 h 45min. After cooling to room temperature, wet methanol (2 mL) was addeddropwise slowly. The resulting clear colorless reaction mixture wasstirred vigorously and heated at 65° C. under a reflux condenser underargon for 34 h. The reaction mixture was loaded directly onto a StrataX-C ion exchange column from Phenomenex. The column was washedsequentially with water, acetonitrile, methanol, and then a mixture of5% ammonium hydroxide in dichloromethane/methanol. Eluent containing thedesired product was concentrated on a rotary evaporator and dried underhigh vacuum at 40° C. to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4) as a white solid. Yield: 92.9 mg, 87%; MS (ESI) m/z 571.4, 573.1.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 158aF)Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 158bF)Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 158cF)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4, 39.5 mg, 0.069 mmol), zinc cyanide (40.6 mg, 0.345 mmol), zincpowder (0.5 mg, 0.007 mmol), Pd₂dba₃ (6.3 mg, 0.007 mmol), dppf (7.7 mg,0.014 mmol), N,N-dimethylformamide (0.90 mL), and water (0.09 mL) werecombined in a 1 dram vial with a stirbar. The reaction mixture wasstirred at room temperature while being sparged with argon gas for 2min. The reaction mixture was sealed, stirred, and heated at 110° C.with a block heater for 22 min. The reaction mixture was diluted withDMSO and methanol, filtered, and purified via preparatory HPLC (15-42%acetonitrile in water with 0.1% TFA). Fractions containing the desiredproduct were loaded onto a Strata X-C ion exchange column fromPhenomenex. The column was washed sequentially with water, acetonitrile,methanol, and then 5% ammonium hydroxide in methanol/dichloromethane.Eluent containing the desired product was concentrated on a rotaryevaporator. The residue was taken up in acetonitrile/water, sonicatedfor a few seconds, and lyophilized to dryness to afford the desiredproduct as a white solid.

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 158aF): Yield: 4.7 mg, 12%; MS (ESI) m/z 562.2, 564.2 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 7.52 (s, 1H), 7.27-7.22 (m, 2H), 7.12-7.06(m, 4H), 7.04-6.95 (m, 3H), 5.74 (s, 1H), 5.43 (br s, 1H), 4.50 (d,J=4.1 Hz, 1H), 3.89 (s, 3H), 3.74 (d, J=14.1 Hz, 1H), 3.16-3.06 (m, 1H),2.80-2.73 (m, 1H), 2.58-2.53 (m, 2H), 2.46-2.39 (m, 2H), 2.15 (dd,J=12.0, 3.0 Hz, 1H), 1.71-1.66 (m, 4H).

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 158bF): Yield: 8.9 mg, 25%; MS (ESI) m/z 518.3 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 7.53-7.49 (m, 2H), 7.37-7.32 (m, 2H), 7.10-7.05 (m,2H), 7.02-6.96 (m, 3H), 6.89 (s, 1H), 5.67 (s, 1H), 5.38 (br s, 1H),4.48 (d, J=4.1 Hz, 1H), 3.84 (s, 3H), 3.79 (d, J=14.1 Hz, 1H), 3.19-3.12(m, 1H), 2.80 (t, J=11.0 Hz, 1H), 2.62-2.56 (m, 2H), 2.48-2.42 (m, 2H),2.19 (d, J=12.0 Hz, 1H), 1.73-1.67 (m, 4H).

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 158cF): Yield: 4.1 mg, 12%; MS (ESI) m/z 509.3 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 7.55 (s, 1H), 7.54-7.49 (m, 2H), 7.37-7.32 (m, 2H),7.11-7.05 (m, 2H), 7.03-6.97 (m, 3H), 5.86 (s, 1H), 4.53 (d, J=4.1 Hz,1H), 3.89 (s, 3H), 3.81 (d, J=14.1 Hz, 1H), 3.22-3.14 (m, 1H), 2.85-2.78(m, 1H), 2.65-2.58 (m, 2H), 2.21 (d, J=12.1 Hz, 1H), 1.74-1.67 (in, 4H).

Example 159Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 159aF)Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 159bF)Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 159cF)

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-N,N-diethyl-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(3)

HATU (75.4 mg, 0.198 mmol) was added to a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 100.6 mg, 0.189 mmol) in N,N-dimethylformamide (1.5 mL) at roomtemperature under argon. After 2 min N,N-diisopropylethylamine (0.082mL, 0.472 mmol) was added. The resulting reaction mixture was stirred atroom temperature under argon for 20 min. Diethylamine (2, 0.039 mL,0.378 mmol) was added and the reaction mixture was stirred at roomtemperature under argon for 20 min. More diethylamine (2, 0.50 mL, 4.83mmol) was added. The resulting reaction mixture was stirred at roomtemperature under argon for 20 min. The reaction mixture was dilutedwith ethyl acetate, washed three times with brine, dried over magnesiumsulfate, filtered, concentrated on a rotary evaporator, and purified viasilica gel chromatography (10-100% EtOAc/hexanes) to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-N,N-diethyl-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(3) as a white foam-solid. Yield: 90.1 mg, 81%; MS (ESI) m/z 587.4,589.2 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((diethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4)

Borane dimethyl sulfide complex (0.145 mL, 1.53 mmol) was added to astirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-N,N-diethyl-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(3, 90.1 mg, 0.153 mmol) in THF (2.5 mL) at room temperature under areflux condenser under argon. Some bubbling was observed. The reactionmixture was heated at 40° C. under a reflux condenser under argon for 8h 45 min. After cooling to room temperature, wet methanol (2 mL) wasadded dropwise slowly. The resulting clear colorless reaction mixturewas stirred vigorously and heated at 65° C. under a reflux condenserunder argon for 11.5 h. The reaction mixture was loaded directly onto aStrata X-C ion exchange column from Phenomenex. The column was washedsequentially with water, acetonitrile, methanol, and then a mixture of5% ammonium hydroxide in dichloromethane/methanol. Eluent containing thedesired product was concentrated on a rotary evaporator and dried underhigh vacuum at 40° C. to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((diethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4) as a white solid. Yield: 72.3 mg, 82%; MS (ESI) r/z 573.2, 575.2[M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 159aF)Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 159bF)Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 159cF)

Rac-(5aR,6S,7,8R,8a)-5a-(4-bromopenyl)-3-chloro-7-((diethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(4, 39.9 mg, 0.070 mmol), zinc cyanide (40.8 mg, 0.348 mmol), zincpowder (0.5 mg, 0.007 mmol), Pd₂dba₃ (6.4 mg, 0.007 mmol), dppf (7.7 mg,0.014 mmol), N,N-dimethylformamide (0.90 mL), and water (0.09 mL) werecombined in a 1 dram vial with a stirbar. The reaction mixture wasstirred at room temperature while being sparged with argon gas for 2min. The reaction mixture was sealed, stirred, and heated at 110° C.with a block heater for 25 min. The reaction mixture was diluted withDMSO and methanol, filtered, and purified via preparatory HPLC (15-43%acetonitrile in water with 0.1% TFA). Fractions containing the desiredproduct were loaded onto a Strata X-C ion exchange column fromPhenomenex. The column was washed sequentially with water, acetonitrile,methanol, and then 5% ammonium hydroxide in methanol/dichloromethane.Eluent containing the desired product was concentrated on a rotaryevaporator. The residue was taken up in acetonitrile/water, sonicatedfor a few seconds, and lyophilized to dryness to afford the desiredproduct as a white solid.

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 159aF): Yield: 5.2 mg, 13%; MS (ESI) m/z 564.2, 566.2 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 7.52 (s, 1H), 7.28-7.22 (m, 2H), 7.13-7.06(m, 4H), 7.04-6.96 (m, 3H), 5.74 (s, 1H), 4.48 (d, J=4.1 Hz, 1H), 3.90(s, 3H), 3.76 (d, J=14.1 Hz, 1H), 3.14-3.07 (m, 1H), 2.66-2.58 (m, 3H),2.47-2.40 (m, 2H), 2.22 (d, J=12.7 Hz, 1H), 0.94 (t, J=7.0 Hz, 6H).

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 159bF): Yield: 9.4 mg, 26%; MS (ESI) m/z 520.3 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 7.54-7.49 (m, 2H), 7.37-7.32 (m, 2H), 7.10-7.04 (m,2H), 7.02-6.97 (m, 3H), 6.89 (s, 1H), 5.66 (s, 1H), 5.28 (s, 1H), 4.45(d, J=4.1 Hz, 1H), 3.85 (s, 3H), 3.81 (d, J=14.0 Hz, 1H), 3.18-3.10 (m,1H), 2.69-2.56 (m, 3H), 2.47-2.40 (m, 2H), 2.27-2.19 (m, 1H), 0.94 (t,J=7.1 Hz, 6H).

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 159cF): Yield: 5.9 mg, 17%; MS (ESI) m/z 511.3 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 7.55 (s, 1H), 7.54-7.49 (m, 2H), 7.38-7.33 (m, 2H),7.11-7.05 (m, 2H), 7.03-6.97 (m, 3H), 5.84 (s, 1H), 4.50 (d, J=4.1 Hz,1H), 3.90 (s, 3H), 3.83 (d, J=14.0 Hz, 1H), 3.21-3.12 (m, 1H), 2.67-2.59(m, 3H), 2.48-2.40 (m, 2H), 2.24 (d, J=12.7 Hz, 1H), 0.95 (t, J=7.0 Hz,6H).

Example 160Rac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 160aF)Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 160bF)

Synthesis ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-6-phenyl-8a-((trimethylsilyl)oxy)-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(2)

In a flame dried flask,rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(1, 300 mg, 0.657 mmol) was dissolved in dichloromethane (4.4 mL) andcooled to 0° C. Diisopropylethylamine (0.24 mL, 1.4 mmol) andtrimethylsilyl trifluoromethanesulfonate (0.15 mL, 0.83 mmol) were addedand the mixture was stirred at 0° C. After 20 min full conversion wasobserved. Water was added, the phases were separated, and the aq. phasewas extracted (3× dichloromethane). The combined organic phases werethen dried (Na₂SO₄), filtered, and concentrated. Purification by columnchromatography (SiO₂, 0-20% ethyl acetate/hexane) to affordrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-6-phenyl-8a-((trimethylsilyl)oxy)-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(2) as a white solid. Yield: 292 mg, 84%; MS (ESI) m/z 527.9 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylthio)-8a-((trimethylsilyl)oxy)-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(3) andrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(4)

In a flame-dried flask, N,N-diisopropylamine (0.06 mL, 0.4 mmol) wasdissolved in THF (2.5 mL) and cooled to 0° C. n-Butyllithium solution(2.5 M in hexane, 0.15 mL, 0.38 mmol) was added, and the mixture wasstirred for 10 min, then cooled down to −78° C. Thenrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-6-phenyl-8a-((trimethylsilyl)oxy)-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(2, 188 mg, 0.355 mmol) in 1.5 mL THF was added, and the mixture wasstirred at −78° C. for 1.5 h. A solution of2-(2-pyridyldisulfanyl)pyridine (102 mg, 0.462 mmol) in 1 mL THF wasadded, and the mixture was allowed to slowly warm up to rt overnight.Then the reaction was quenched with NH₄Cl(aq). The mixture was extractedwith dichloromethane thrice, and the combined organic phases were dried(Na₂SO₄), filtered and concentrated. Purification by columnchromatography (SiO₂, 0-40% ethyl acetate/hexane) to affordrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylthio)-8a-((trimethylsilyl)oxy)-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(3). Yield: (87 mg, 0.14 mmol, 39%); MS (ESI) m/z 637.0 [M+1]⁺, andrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(4).Yield: 46 mg (0.081 mmol), 23%; MS (ESI) m/z 565.0 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one (4) viadesilylation of (3)

The starting materialrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylthio)-8a-((trimethylsilyl)oxy)-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(3, 79.3 mg, 0.124 mmol) was dissolved in THF (2.5 mL), cooled to 0° C.,and treated with tetrabutylammonium fluoride (1.0 M in THF, 0.14 mL,0.14 mmol). The mixture was stirred at rt. After 15 min full and cleanconversion was observed by TLC. The reaction was quenched (NH₄Cl(aq))and the mixture was extracted with dichloromethane (3×). The combinedorganic phases were dried (Na₂SO₄), filtered and concentrated. The crudeproduct was combined with the crude product from an analogouslyconducted reaction with 5.3 mg (0.0083 mmol) starting material forpurification purposes. Purification by column chromatography (SiO₂,0-50% ethyl acetate/hexane) to affordrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(4) as a white solid. Yield: 74.2 mg (0.131 mmol, 99%); MS (ESI) m/z 565[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 160aF) andrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 160bF)

The starting materialrac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(4, 33 mg, 0.058 mmol) was dissolved in methanol (1 mL) and cooled to 0°C. NaBH₄ (22 mg, 0.58 mmol) was added, and the mixture was stirred at 0°C. After 10 min complete conversion was observed; LCMS showed ratherclean conversion to a mixture of diastereomeric alcohols 5:6 (ratio 5:6ca. 1:9). The mixture was directly subjected to column chromatography(SiO₂, 0-40% ethyl acetate/hexane) to give 12.3 mg of slightly impuresyn-diol (Cpd. No. 160bF) and 3 mg of slightly impure anti-diol (Cpd.No. 160aF). Syn-diol (Cpd. No. 160bF) was re-purified by reverse phaseHPLC (C18, MeCN/water+0.1% TFA) and finally preparative TLC to affordpurerac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 160bF) as a white solid. Yield: 4.1 mg; MS (ESI) m/z 567.0[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (d, J=2.0 Hz, 1H), 8.13-8.10(m, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.56 (ddd, J=7.6, 7.6, 2.0 Hz, 1H),7.40 (d, J=8.7 Hz, 2H), 7.22 (d, J=8.7 Hz, 2H), 7.07 (ddd, J=7.6, 4.9,1.0 Hz, 1H), 7.04-6.97 (m, 4H), 6.82-6.77 (m, 2H), 6.65 (d, J=5.1 Hz,1H), 5.60 (s, 1H), 4.90 (dd, J=6.8, 5.1 Hz, 1H), 4.46 (dd, J=14.2, 6.8Hz, 1H), 3.73 (d, J=14.2 Hz, 1H). Anti-diol (Cpd. No. 160aF) wasrepurified by preparative TLC (SiO₂, dichloromethane/MeOH=19/1) toafford purerac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 160aF) as a white solid. Yield: 1.2 mg; MS (ESI) m/z 567.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (bd, J=5.1 Hz, 1H), 8.19 (d,J=2.1 Hz, 1H), 7.66 (d, J=2.1 Hz, 1H), 7.63 (ddd, J=7.9, 7.9, 2.1 Hz,1H), 7.29-7.23 (m, 3H), 7.18 (bdd, J=7.9 Hz, 5.1 Hz, 1H), 7.14 (d, J=8.6Hz, 2H), 7.03-6.94 (m, 5H), 6.26 (s, 1H), 5.93 (d, J=5.9 Hz, 1H), 5.50(dd, J=14.7, 4.0 Hz, 1H), 4.47 (dd, J=5.9, 4.0 Hz, 1H), 4.29 (d, J=14.7Hz, 1H).

Example 161 Rac-methyl(1aS,2R,3S,3aR,8bS)-3a-(4-bromophenyl)-6-chloro-3-phenyl-1a,2,3,3a-tetrahydro-oxireno[2″,3″:1′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-2-carboxylate (Cpd. No. 161F)

Synthesis of rac-methyl(1aS,2R,3S,3aR,8bS)-3a-(4-bromophenyl)-6-chloro-3-phenyl-1a,2,3,3a-tetrahydro-oxireno[2″,3″:1′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-2-carboxylate(Cpd. No. 161F)

Rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(1, 42 mg, 0.081 mmol) was dissolved in dichloromethane (0.6 mL) underargon. Martin sulfurane (82 mg, 0.12 mmol) was added, and the mixturewas stirred at rt. The mixture turned dark red. After 6 h the reactionwas quenched with NH₄Cl(aq). The mixture was extracted withdichloromethane (3×), and the combined organic phases were dried(Na₂SO₄), filtered and concentrated. Purification by repeated columnchromatography (SiO₂, 0-30% ethyl acetate/hexane, then 0-20% ethylacetate/hexane) to afford rac-methyl(1aS,2R,3S,3aR,8bS)-3a-(4-bromophenyl)-6-chloro-3-phenyl-1a,2,3,3a-tetrahydro-oxireno[2″,3″:1′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridine-2-carboxylate (Cpd. No.161F) as a light orange solid. Yield: 29.6 mg (0.0594 mmol), 73%; MS(ESI) m/z 498.0 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J=1.9 Hz,1H), 7.29 (d, J=1.9 Hz, 1H), 7.23-7.19 (m, 2H), 7.15-7.10 (m, 5H),7.05-7.00 (m, 2H), 4.91 (d, J=11.8 Hz, 1H), 4.37 (d, J=0.6 Hz, 1H), 3.72(s, 3H), 3.72 (dd, J=11.8, 0.6 Hz, 1H).

Example 162Rac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 162F)

Synthesis ofrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(2)

The starting materialrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-6,7-dihydrocyclopenta[4,5]furo[1,2-b]pyridin-8-one(1, 209 mg, 0.458 mmol) was dissolved in acetic acid (2 mL) and MeCN (2mL), and sodium triacetoxyborohydride (0.97 g, 4.6 mmol) was added.After stirring for 20 min water was carefully added. The mixture wasextracted with dichloromethane thrice, and the combined organic phaseswere dried (Na₂SO₄), filtered and concentrated. Purification by columnchromatography (SiO₂, 0-30% ethyl acetate/hexane) to affordrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(2). Yielded: 196 mg (0.427 mmol), 93%; MS (ESI) m/z 458.1 [M+1]⁺.

Synthesis ofrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylmethanesulfonate (3)

To a solution ofrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(2, 196 mg, 0.427 mmol) in pyridine (4.5 mL) was added methanesulfonylchloride (0.04 mL, 0.5 mmol) and the mixture was stirred at rt Afterstirring over night the reaction was quenched with NH₄Cl(aq) and themixture was extracted with dichloromethane thrice. The combined organicphases were dried (Na₂SO₄), filtered and concentrated. Purification bycolumn chromatography (SiO₂, 0-50% ethyl acetate/hexane) to affordrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylmethanesulfonate (3) as a white solid. Yield:185 mg (0.345 mmol), 81%;MS (ESI) m/z 535.9 [M+1]⁺.

Synthesis ofrac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(4)

To a solution ofrac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylmethanesulfonate (3, 185 mg, 0.345 mmol) in DMSO (3.5 mL) was addedpotassium cyanide (45 mg, 0.69 mmol) and the mixture was stirred at rtunder argon. After 1.5 h the mixture was diluted with ethyl acetate andwashed with water and brine, then dried (Na₂SO₄), filtered andconcentrated. Purification by column chromatography (SiO₂, 0-45% ethylacetate/hexane) to affordrac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(4) as off-white solid. Yield: 149 mg (0.319 mmol), 92%; MS (ESI) m/z467.1 [M+1]⁺.

Synthesis ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbaldehyde(5)

The starting materialrac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(4, 20 mg, 0.043 mmol) was dissolved in dichloromethane (0.4 mL) andcooled to −78° C. DIBAL (1 M sin. in toluene) (0.1 mL, 0.1 mmol) wasadded, and the mixture was stirred at −78° C. After 2.5 h another 0.05mL DIBAL sln (1 M in toluene, 0.05 mmol) were added. After another 30min the mixture was allowed to warm up to −20° C. within 1 h. Then MeOH(0.1 mL) was added, followed by ca. 2 mL aq. sat. Rochelle-salt sln. Themixture was stirred for 1 h at rt, then extracted (3× dichloromethane).The combined organic phases were dried (Na₂SO₄), filtered andconcentrated. The crude product, which contained a diastereomericmixture of the C1-aldehydes (5), was directly used in the next step.

Synthesis ofrac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 162F)

Cruderac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbaldehyde(5) from the previous step was dissolved in methanol (1 mL) under argonand cooled to 0° C. Sodium borohydride (16 mg, 0.42 mmol) was added andthe mixture was stirred at 0° C. for 20 min, then at rt. After 45 mintotal reaction time the reaction was quenched with water, and theresulting mixture was extracted thrice with ethyl acetate. The combinedorganic phases were dried (Na₂SO₄), filtered and concentrated.Purification by preparative TLC (SiO₂, EtOAC/Hexane=1/1) over 2 steps toafford primary alcohol ofrac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 162F) as a white solid. Yield: 1.3 mg (0.0028 mmol), 6%; MS(ESI) m/z 472.1 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J=2.1 Hz,1H), 7.75 (d, J=2.1 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 7.14 (d, J=8.7 Hz,1H), 7.13-7.07 (m, 3H), 7.00-6.97 (m, 2H), 5.57 (s, 1H), 4.55 (bt, J=5.4Hz, 1H), 4.07-4.01 (m, 1H), 3.85-3.76 (m, 1H), 3.55 (dd, J=14.0, 6.2 Hz,1H), 2.73-2.63 (m, 1H), 2.35 (ddd, J=13, 13, 13 Hz, 1H), 2.24 (ddd,J=13, 6.5, 6.5 Hz, 1H).

Example 163Rac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylsulfonyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 163F)

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (2)

To rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate,(1, 400 mg, 0.774 mmol) in methanol (3 mL) and THF (3 mL) at rt wasadded LiOH (aq) (2 M, 6 mL, 12 mmol) and the mixture was stirred at 40°C. After 1 h the mixture was cooled down to rt, stirred for another 1.5h, acidified with 2M hydrochloric acid (aq) (6.5 mL) and diluted withEtOAc and water. The aq. phase was extracted thrice (EtOAc), and thecombined organic phases were dried (Na₂SO₄), filtered and concentratedto afford the crude acid ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (2). Yield: 416 mg; MS (ESI) m/z 502.0 [M+1]⁺. The crude productwas used in the next step without further purification.

Synthesis of rac-2-thioxopyridin-1(2H)-yl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(3)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (2, 416 mg of the crude product obtained in the previous step) and1-hydroxypyridine-2-thione (112 mg, 0.881 mmol) in dichloromethane (7.5mL) in a vial shielded from light was added DCC (176 mg, 0.851 mmol) andthe mixture was stirred at r.t. overnight. After 17.5 h the mixture wasconcentrated and the residue was taken up in MeCN and filtered throughcelite. The filtrate was concentrated. Purification by columnchromatography (SiO₂, 0-50% ethyl acetate/hexane; column was covered inaluminum foil) yielded 464 mg (0.758 mmol, 98% over 2 steps) ofrac-2-thioxopyridin-1(2H)-yl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(3) as a yellow/green solid; MS (ESI) m/z 611 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (4)

Rac-2-thioxopyridin-1(2H)-yl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(3, 56 mg, 0.092 mmol) was dissolved in dichloromethane (2.5 mL) in a 5mL MW vial under argon. The vial was sealed and the mixture was stirredand irradiated (HDX XG-1026 lamp, 250 W halogen bulb, 1 h). After 20 mincomplete conversion was observed by LCMS. The mixture was concentratedand the crude product was purified by column chromatography (SiO₂, 0-50%ethyl acetate/hexane) to yield 42.3 mg (0.0745 mmol, 81%) ofrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(4) as a white solid; MS (ESI) rm/z 566.9 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylsulfonyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 163F)

Rac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylthio)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(4, 42.3 mg, 0.0745 mmol) was dissolved in methanol (2 mL) and cooled to0° C. Hydrogen peroxide (30% in water, 0.07 mL, 0.7 mmol) was added,followed by sodium tungstate dihydrate (12.3 mg, 0.0373 mmol), and themixture was stirred at rt. After 25 h water was added, and the mixturewas extracted with dichloromethane thrice. The combined organic phaseswere dried (Na₂SO₄), filtered and concentrated. Purification by columnchromatography (SiO₂, 0-50% ethyl acetate/dichloromethane) yieldedproduct contaminated with the sulfoxide intermediate (inseparable). Thematerial was re-subjected to the same reaction conditions. After 9 h 1mL N,N-dimethylformamide was added to improve solubility. After another1.5 h another 0.07 mL hydrogen peroxide (30% in water, 0.7 mmol) wereadded and the mixture was stirred overnight. Then another 0.07 mLhydrogen peroxide (30% in water, 0.7 mmol) were added. After 2 daystotal the reaction was complete as judged by LCMS. The mixture wasdiluted with water and extracted with dichloromethane (3×). The combinedorganic phases were dried (Na₂SO₄), filtered and concentrated.Purification by column chromatography (SiO₂, 0-40% ethylacetate/dichloromethane) yielded 18.4 mg (41%) ofRac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylsulfonyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 163F) as white solid; MS (ESI) m/z 598.9 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 8.80 (ddd, J=4.7, 1.7, 1.0 Hz, 1H), 8.19 (d, J=2.0 Hz,1H), 7.79 (ddd, J=7.7, 7.7, 1.7, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.64 (ddd,J=7.7, 4.7, 1.0 Hz, 1H), 7.40 (ddd, J=7.7, 1.0, 1.0 Hz, 1H), 7.24 (d,J=8.8 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 6.89-6.83 (m, 1H), 6.77 (t, J=7.3Hz, 2H), 6.65 (d, J=7.3 Hz, 2H), 6.50 (s, 1H), 6.11 (d, J=6.2 Hz, 1H),5.26 (dd, J=13.7, 4.3 Hz, 1H), 4.80 (dd, J=6.2, 4.3 Hz, 1H), 4.69 (d,J=13.7 Hz).

Example 164Rac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyridin-2-ylsulfonyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 164F)

Synthesis ofrac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyridin-2-ylsulfonyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 164F)

In a 0.5-2 mL microwave vialrac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2-ylsulfonyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(1, 50 mg, 0.083 mmol) was dissolved in N,N-dimethylformamide (0.8 mL)and water (0.08 mL). Zinc cyanide (33 mg, 0.28 mmol) and zinc (3 mg,0.05 mmol) were added, and the mixture was degassed by bubbling argonthrough it for 5 min. Dppf (14 mg, 0.025 mmol) andTris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.012 mmol) were added,and the mixture was degassed for another 5 min, then incubated at 100°C. for 1 h 15 min in total. Then the mixture was diluted withdichloromethane and washed with water. The aq. phase was extracted withdichloromethane twice. Then the combined organic phases were dried(Na₂SO₄), filtered and concentrated. Purification by columnchromatography (SiO₂, 0-50% ethyl acetate/dichloromethane) yielded 16.3mg ofrac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyridin-2-ylsulfonyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 164) containing traces of SM. This material was repurified byHPLC (C18, MeCN/water+0.1% TFA) to give 10 mg (0.018 mmol, 22%) of purerac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyridin-2-ylsulfonyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 164F) as a white solid; MS (ESI) m/z 546.2 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) d 8.80 (ddd, J=4.7, 1.7, 1.0 Hz, 1H), 8.20 (d, J=2.0 Hz,1H), 7.81 (ddd, J=7.8, 7.8, 1.7 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.65(ddd, J=7.8, 4.7, 1.0 Hz, 1H), 7.50 (d, J=8.7 Hz, 2H), 7.43 (ddd, J=7.8,1.0, 1.0 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 6.89-6.84 (m, 1H), 6.78 (t,J=7.5 Hz, 2H), 6.71-6.67 (m, 2H), 6.59 (b, 1H), 6.14 (b, 1H), 5.33 (dd,J=13.8, 4.3, 1H), 4.80 (d, J=4.3 Hz, 1H), 4.75 (d, J=13.8 Hz, 1H).

Example 165Rac-(5aR,6S,8S,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetra-hydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 165)

Synthesis ofrac-(5aR,6S,8S,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetra-hydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 165F)

To a solution ofrac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(1, 20 mg, 0.043 mmol) in THF (0.5 mL) at 0° C. was added LAH (3.4 mg,0.090 mmol) and the mixture was stirred at rt. After 1 h 0.02 mL waterwere added at 0° C., followed by 0.02 mL 12.5% NaOH (aq) and ca. 60 mgof Na₂SO₄. The mixture was stirred for 10 min at rt, then filteredthrough celite (rinsed with dichloromethane) and concentrated. The crudeproduct (ca. 19 mg, yellow foam) was purified by repeated HPLC (C18,MeCN/H₂O+0.1% TFA) to yield 5.3 mg (0.0091 mmol, 21%) of the TFA salt ofrac-(5aR,6S,8S,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetra-hydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 165F) as a white solid; MS (ESI) m/z 470.9 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 8.30 (d, J=2.0 Hz, 1H), 8.01 (b, 3H), 7.88 (d, J=2.0 Hz,1H), 7.38 (d, J=8.8 Hz, 2H), 7.16-7.08 (m, 5H), 6.96-6.92 (m, 2H), 6.01(s, 1H), 3.74 (dd, J=9.9, 8.5 Hz, 1H), 3.56-3.47 (m, 1H), 3.20-3.10 (m,1H), 3.08-2.97 (m, 1H), 2.60 (ddd, J=14.0, 9.9, 9.9 Hz, 1H), 1.86 (ddd,J=14.0, 8.5, 6.2, 1H).

Example 166Rac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 166F)

Synthesis ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbaldehyde(2)

The starting materialrac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(1, 84 mg, 0.18 mmol) was dissolved in dichloromethane (1.8 mL) andcooled to −78° C. DIBAL (1.0 M sln. in toluene, 0.39 mL, 0.39 mmol) wasadded, and the mixture was stirred at −78° C. for 30 min, then warmed upto 0° C. within 30 min and stirred for another 30 min. Then 2M aq.hydrochloric acid (0.7 mL) was added dropwise, and the mixture wasdiluted with saturated aq. Rochelle salt solution and dichloromethaneand vigorously stirred for 30 min. Then the mixture was extracted withdichloromethane thrice. The combined organic phases were washed withbrine, dried (Na₂SO₄), filtered and concentrated. The crude product(mixture of epimers) ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbaldehyde(2) was directly used in the next step without further purification.

Synthesis ofrac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 166F)

The starting materialrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbaldehyde(2) (crude product from previous step) was dissolved in methanol (1.8mL) under argon and cooled to 0° C. Sodium borohydride (34 mg, 0.90mmol) was added and the mixture was stirred at 0° C. for 20 min, then atrt for 5 min. Complete conversion was observed by TLC(hexane/EtOAc=1/1). The reaction was quenched at 0° C. (water), and themixture was extracted (3× dichloromethane). The combined organic phaseswere dried (Na₂SO₄), filtered and concentrated. Purification by columnchromatography (SiO₂, 0-10% ethyl acetate/dichloromethane) yielded 14.6mg (ca. 0.03 mmol, ca. 17%) of slightly impure product, which wasrepurified by HPLC (C18, MeCN/water+0.1% TFA) and finally preparativeTLC (SiO₂, EtOAc/Hexane=1/1) to give 3.7 mg (0.0078 mmol) of purerac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 166F) as a white solid; MS (ESI) m/z 472.0 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 8.26 (d, J=2.0 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.35 (d,J=8.8 Hz, 1H), 7.14 (d, J=8.8 Hz, 2H), 7.12-7.07 (m, 3H), 6.97-6.92 (m,2H), 5.98 (s, 1H), 4.79 (dd, J=6.9, 4.4 Hz, 1H), 4.05 (ddd, J=10.8, 5.9,4.4 Hz, 1H), 3.61 (dd, J=12.0, 7.6 Hz, 1H), 3.48-3.40 (m, 1H), 2.95-2.84(m, 1H), 2.60-2.47 (m, 1H), 1.89 (ddd, J=13.5, 7.6, 3.6 Hz, 1H).

Example 167Rac-4-((5aR,6S,8R,8aR)-3-chloro-8a-hydroxy-8-(hydroxymethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 167F)

Synthesis ofrac-4-((5aR,6S,8R,8aR)-3-chloro-8a-hydroxy-8-(hydroxymethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 167F)

In a 0.5-2 mL microwave vialrac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(1, 12.7 mg, 0.0269 mmol) was dissolved in N,N-dimethylformamide (0.5mL) and water (0.05 mL). Zinc cyanide (11 mg, 0.094 mmol) and zinc (1mg, 0.02 mmol) were added, and the mixture was degassed by bubblingargon through it for 5 min. Dppf (4.6 mg, 0.0083 mmol) andTris(dibenzylideneacetone)dipalladium(0) (3.5 mg, 0.0039 mmol) wereadded and the mixture was degassed for another 5 min, then incubated at100° C. for 1 h 10 min. Then the mixture was diluted withdichloromethane and washed with water. The aq. phase was extracted withdichloromethane twice. The combined organic phases were dried (Na₂SO₄),filtered and concentrated. Purification by column chromatography (SiO₂,0-50% ethyl acetate/hexane) yielded 3.8 mg (0.0091 mmol, 34%) ofrac-4-((5aR,6S,8R,8aR)-3-chloro-8a-hydroxy-8-(hydroxymethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 167F) as a white solid; MS (ESI) m/z 419.2 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 8.27 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.59 (d,J=8.7 Hz, 2H), 7.39 (d, J=8.7 Hz, 2H), 7.12-7.03 (m, 3H), 7.00-6.96 (m,2H), 5.66 (s, 1H), 4.59 (dd, J=6.1, 4.8 Hz, 1H), 4.06 (ddd, J=11.0, 4.8,4.8 Hz, 1H), 3.84 (ddd, J=11.0, 7.8, 6.1 Hz, 1H), 3.63 (dd, J=14.0, 6.2Hz, 1H), 2.74-2.65 (m, 1H), 2.40 (b ddd, J=13, 13, 13 Hz, 1H), 2.26 (bddd, J=13, 6.5, 6.5 Hz, 1H).

Example 168Rac-4-((5aR,6S,8S,8aR)-3-chloro-8a-hydroxy-8-(hydroxymethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 168F)

Sysnthesis ofrac-4-((5aR,6S,8S,8aR)-3-chloro-8a-hydroxy-8-(hydroxymethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 168F)

In a 0.5-2 mL microwave vialrac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8-(hydroxymethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(1, 12.4 mg, 0.0262 mmol) was dissolved in N,N-dimethylformamide (0.5mL) and water (0.05 mL). Zinc cyanide (10.5 mg, 0.0894 mmol) and zinc (1mg, 0.02 mmol) were added, and the mixture was degassed by bubblingargon through it for 5 min. Dppf (4.5 mg, 0.0081 mmol) andTris(dibenzylideneacetone)dipalladium(0) (3.5 mg, 0.0038 mmol) wereadded and the mixture was degassed for another 5 min, then incubated at100° C. for 45 min in total. Then the mixture was diluted withdichloromethane and washed with water. The aq. phase was extracted withdichloromethane twice. Then the combined organic phases were dried(Na₂SO₄), filtered and concentrated. Purification by columnchromatography (SiO₂, 0-50% ethyl acetate/hexane) and preparative TLC(SiO₂, EtOAC/Hexane=2/1) yielded 3.8 mg (0.0091 mmol, 35%) ofrac-4-((5aR,6S,8S,8aR)-3-chloro-8a-hydroxy-8-(hydroxymethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 168F) as a white solid; MS (ESI) m/z 419.1 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 8.28 (d, J=2.0 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.63 (d,J=8.8 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 7.13-7.06 (m, 3H), 6.96-6.92 (m,2H), 5.77 (s, 1H), 4.79 (dd, J=6.9, 4.4 Hz, 1H), 4.07-4.01 (m, 1H), 3.69(dd, J=12.1, 7.7 Hz, 1H), 3.49-3.41 (m, 1H), 2.98-2.89 (m, 1H),2.65-2.54 (m, 1H), 1.93 (ddd, J=13.4, 7.7, 3.6 Hz, 1H).

Example 169Rac-(2aR,3S,3aR,8bS,8cR)-3a-(4-bromophenyl)-6-chloro-8b-hydroxy-3-phenyl-3,3a,8b,8c-tetrahydrooxeto[3″,2′:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-2(2aH)-one(Cpd. No. 169F)

Synthesis ofrac-(2aR,3S,3aR,8bS,8cR)-3a-(4-bromophenyl)-6-chloro-8b-hydroxy-3-phenyl-3,3a,8b,8c-tetrahydrooxeto[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-2(2aH)-one(Cpd. No. 169F)

The starting materialrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (1, 106 mg, 0.211 mmol) was dissolved in dichloromethane (3.8 mL)under argon and cooled to 0° C. Triethylamine (0.09 mL, 0.6 mmol) and3-[chloro-(2-oxooxazolidin-3-yl)phosphoryl]oxazolidin-2-one (70 mg, 0.27mmol) were added, and the mixture was stirred at rt. After 1 h 15 minwater and brine were added, and the mixture was extracted withdichloromethane thrice. The combined organic phases were dried (Na₂SO₄),filtered and concentrated. Purification by column chromatography (SiO₂,0-30% ethyl acetate/hexane) yielded 53.9 mg (0.111 mmol, 53%) ofrac-(2aR,3S,3aR,8bS,8cR)-3a-(4-bromophenyl)-6-chloro-8b-hydroxy-3-phenyl-3,3a,8b,8c-tetrahydrooxeto[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[3,2-b]pyridin-2(2aH)-one(Cpd. No. 169F) as a white solid; MS (ESI) m/z 484.2 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 8.24 (d, J=2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.36 (s,1H), 7.24 (d, J=8.9 Hz, 2H), 7.21-7.16 (m, 3H), 7.10-7.05 (m, 4H), 5.46(d, J=5.0 Hz, 1H), 4.89 (dd, J=5.0, 2.9 Hz, 1H), 4.26 (d, J=2.9 Hz, 1H).

Example 170Rac-(4bR,5R,6R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 170F)

Synthesis of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-5-((methylsulfonyl)oxy)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(2)

To a solution of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(1, 800 mg, 1.56 mmol) in pyridine (15 mL) was added methanesulfonylchloride (0.14 mL, 1.8 mmol) and the mixture was stirred at rt. After 24h, another 0.03 mL (0.4 mmol) methanesulfonyl chloride added, and themixture was stirred for another 1 h. Then the reaction was quenched withNH₄Cl(aq) and the mixture was extracted with dichloromethane thrice. Thecombined organic phases were dried (Na₂SO₄), filtered and concentrated.The crude product rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-5-((methylsulfonyl)oxy)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(2); MS (ESI) m/z 589.9 [M+1]⁺; was dried under vacuum overnight andthen directly used in the next step.

Synthesis of rac-methyl(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-cyano-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(3)

To a solution of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-5-((methylsulfonyl)oxy)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(2, crude product from previous step) in DMSO (15 mL) was addedpotassium cyanide (226 mg, 3.47 mmol) and the mixture was stirred at rtunder argon. After 6 h the mixture was diluted with EtOAc and washedbrine twice, then dried (Na₂SO₄), filtered and concentrated.Purification by column chromatography yielded 755 mg (1.45 mmol, 93%over 2 steps) of rac-methyl(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-cyano-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(3); MS (ESI) m/z 521.3 [M+1]⁺.

Synthesis ofrac-(4bR,5R,6R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 170F)

To a solution of rac-methyl(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-cyano-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(3, 40 mg, 0.077 mmol) in THF (0.8 mL) at 0° C. was added LAH (11.7 mg,0.306 mmol) and the mixture was stirred at rt. After 1 h 0.05 mL waterwere added at 0° C., followed by 0.05 mL 12.5% NaOH (aq) and ca. 150 mgof Na₂SO₄. The mixture was stirred for 10 min at rt, then filteredthrough celite (rinsed with dichloromethane) and concentrated. The crudeproduct (ca. 34 mg, white solid) was purified by HPLC (C18,MeCN/H₂O+0.1% TFA) to yield 32.5 mg (0.0532 mmol, 69%) ofrac-(4bR,5R,6R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 170F) as the TFA salt; MS (ESI) m/z 497.2 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 8.21 (s, 1H), 8.14 (s, 1H), 7.72 (s, 3H), 7.36 (d, J=8.7Hz, 2H), 7.15-7.06 (m, 5H), 6.83-6.77 (m, 2H), 6.30 (s, 1H), 4.90 (b,1H), 4.01 (s, 3H), 3.54-3.41 (m, 1H), 3.46 (dd, J=11.3, 2.9 Hz, 1H),3.35-3.28 (m, 1H), 3.29 (d, J=13.7 Hz, 1H), 3.17 (dd, J=11.3, 5.5 Hz,1H), 2.99 (ddd, J=9.9, 9.9, 4.0 Hz, 1H), 2.64-2.54 (m, 1H).

Example 171Rac-4-((4bR,5R,6R,7S,7aR)-5-(aminomethyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 171F)

Synthesis ofrac4-((4bR,5R,6R,7S,7aR)-5-(aminomethyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 171F)

In a 0.5-2 mL microwave vialrac-(4bR,5R,6R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 91 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (3.3 mL)and water (0.33 mL). Zinc cyanide (90 mg, 0.77 mmol) and zinc (4.8 mg,0.073 mmol) were added, and the mixture was degassed by bubbling argonthrough it for 5 min. Dppf (31 mg, 0.056 mmol) andTris(dibenzylideneacetone)dipalladium(0) (24.1 mg, 0.0263 mmol) wereadded and the mixture was degassed for another 5 min, then incubated at100° C. for 1.5 h. Then the mixture was filtered (rinsed with MeCN) andconcentrated. The crude product was purified by HPLC (C18,MeCN/water+0.1% TFA) to yield 46.1 mg (0.0827 mmol), 45% ofrac-4-((4bR,5R,6R,7S,7aR)-5-(aminomethyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 171F) as the TFA salt (white solid); MS (ESI) m/z 444.2[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (s, 1H), 8.15 (s, 1H), 7.68 (b,3H), 7.63 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.3 Hz, 2H), 7.12-7.06 (m, 3H),6.83-6.78 (m, 2H), 6.36 (s, 1H), 4.88 (b, 1H), 4.01 (s, 3H), 3.56-3.49(m, 1H), 3.49-3.44 (m, 1H), 3.35 (d, J=13.5 Hz, 1H), 3.37-3.27 (m, 1H),3.19 (dd, J=11.4, 5.4, 1H), 3.00 (ddd, J=10.0, 10.0, 4.0, 1H), 2.70-2.61(m, 1H).

Example 172Rac-(4bR,5R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 172F)

Synthesis ofrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-cyano-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (2)

To rac-methyl(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-cyano-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(1,467 mg, 0.896 mmol) in methanol (4.5 mL) and THF (4.5 mL) at rt wasadded LiOH (aq) (2M, 6.5 mL, 13 mmol) and the mixture was stirred at 40°C. After 40 min the mixture was cooled down to rt, acidified with 2Mhydrochloric acid (aq) (7 mL) and diluted with EtOAc and water. The aq.phase was extracted thrice, and the combined organic phases were dried(Na₂SO₄), filtered and concentrated to afford cruderac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-cyano-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (2) as an orange solid. Yield: 457 mg; MS (ESI) m/z 507.2 [M+1]⁺.The crude material was pure by LCMS and was used without furtherpurification.

Synthesis ofrac-(4bR,5R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-5-carbonitrile(3)

In an 8-mL-vial, cruderac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-cyano-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (2, 100 mg) and 1-hydroxypyridine-2-thione (37.3 mg, 0.294 mmol)were suspended in chloroform (2.8 mL). 2-methylpropane-2-thiol (0.67 mL,0.56 g, 5.9 mmol) was added, the mixture was irradiated (HDX XG-1026lamp, 250 W halogen bulb), and a solution of DCC (46 mg, 0.22 mmol) in 2mL CHCl₃ was added dropwise under argon. The mixture was irradiated withvigorous stirring without additional external heating. After 10 mincomplete conversion was observed. The mixture was concentrated and driedin vacuo. The crude product was combined with the crude product of ananalogously conducted experiment utilizing 15 mg (0.030 mmol) ofstarting material for purification purposes. Purification by HPLC (C18,MeCN/water+0.1% TFA) yielded 73 mg (0.16 mmol, 69%) ofrac-(4bR,5R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-5-carbonitrile(3) as a white foam; MS (ESI) m/z 463.1 [M+1]⁺.

Synthesis ofrac-(4bR,5R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 172F)

To a solution ofrac-(4bR,5R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-5-carbonitrile(3, 73 mg, 0.16 mmol) in THF (1.6 mL) at 0° C. was added LAH (16.5 mg,0.435 mmol) and the mixture was stirred at rt. After 30 min 0.05 mLwater were added at 0° C., followed by 0.05 mL 12.5% NaOH (aq) and ca.100 mg of Na₂SO₄. The mixture was stirred for 10 min at rt, thenfiltered through celite (rinsed with dichloromethane) and concentrated.Purification of the crude product by HPLC (C18, MeCN/H₂O+0.1% TFA)yielded 61.4 mg (ca. 93% pure by ¹H-NMR, 0.0982 mmol, 62% yield) ofrac-(4bR,5R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 172F) as the TFA salt. An analytically pure sample could beobtained by repurification of 12 mg of this material by reverse phaseHPLC; MS (ESI) m/z 467.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (s,1H), 8.12 (s, 1H), 7.72 (b, 3H), 7.33 (d, J=8.8 Hz, 2H), 7.15-7.05 (m,5H), 6.96-6.92 (m, 2H), 6.05 (s, 1H), 3.99 (s, 3H), 3.56-3.40 (m, 2H),3.22-3.12 (m, 1H), 2.96-2.86 (m, 1H), 2.29-2.22 (m, 2H).

Example 173Rac-4-((4bR,5R,7S,7aR)-5-(aminomethyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 173F)

Synthesis of rac-tert-butyl(((4bR,5R,7S,7aR)-7a-(4-cyanophenyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-yl)methyl)carbamate(2)

In a 0.5-2 mL microwave vialrac-(4bR,5R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 35.6 mg, 0.06000 mmol) was dissolved in N,N-dimethylformamide (1.5mL) and water (0.15 mL). Zinc cyanide (30 mg, 0.26 mmol) and zinc (2.1mg, 0.032 mmol) were added, and the mixture was degassed by bubblingargon through it for 5 min. Dppf (10.5 mg, 0.0189 mmol) andTris(dibenzylideneacetone)dipalladium(0) (8.1 mg, 0.0088 mmol) wereadded and the mixture was degassed for another 5 min, then incubated at100° C. for 1 h. Then the mixture was filtered and concentrated. Thecrude product was dissolved in dichloromethane (0.6 mL), andN,N-diisopropylethylamine (0.06 mL, 0.3 mmol) and tert-butoxycarbonyltert-butyl carbonate (22 mg, 0.10 mmol) were added at 0° C. The mixturewas stirred at rt. After 1 h 45 min water was added. The mixture wasextracted with dichloromethane thrice, and the combined organic phaseswere dried (Na₂SO₄), filtered and concentrated. Purification by HPLC(C18, MeCN/H₂O+0.1% TFA) yielded 13 mg (0.025 mmol, 41% over 2 steps) ofrac-tert-butyl(((4bR,5R,7S,7aR)-7a-(4-cyanophenyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-yl)methyl)carbamate(2) as a white solid; MS (ESI) m/z 514.4 [M+1]⁺.

Synthesis ofrac-4-((4bR,5R,7S,7aR)-5-(aminomethyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 173F)

To a solution of rac-tert-butylN-[[(5aR,6S,8R,8aR)-5a-(4-cyanophenyl)-8a-hydroxy-1-methoxy-6-phenyl-7,8-dihydro-6H-cyclopenta[4,5]furo[1,2-b]pyridin-8-yl]methyl]carbamate(2, 13 mg, 0.025 mmol) in dichloromethane (0.8 mL) at rt was addedtrifluoroacetic acid (0.04 mL, 0.06 g, 0.5 mmol) and the mixture wasstirred at rt. After 1.5 h another 0.04 mL (0.06 g, 0.5 mmol)trifluoroacetic acid were added. After another 30 min another 0.02 mL(0.03 g, 0.3 mmol) trifluoroacetic acid were added, and the mixture wasstirred for another 45 min, after which the reaction was complete asjudged by LCMS. The mixture was concentrated, taken up in MeCN andwater, frozen and lyophilized to yield 11.7 mg (0.0222 mmol, 87%) of theTFA salt ofrac-4-((4bR,5R,7S,7aR)-5-(aminomethyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 173F) as a white solid; MS (ESI) m/z 414.3 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 8.23 (s, 1H), 8.14 (s, 1H), 7.72 (b, 3H), 7.61 (d, J=8.0Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.15-7.04 (m, 3H), 6.97-6.92 (m, 2H),6.12 (s, 1H), 3.99 (s, 3H), 3.65-3.55 (m, 1H), 3.52-3.42 (m, 1H),3.26-3.14 (m, 1H), 2.98-2.87 (m, 1H), 2.36-2.25 (m, 2H).

Example 174Rac-(5aR,6S,8R,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 174F)

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-((methylsulfonyl)oxy)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(1, 800 mg, 1.55 mmol) in pyridine (15 mL) was added methanesulfonylchloride (0.15 mL, 0.22 g, 1.9 mmol) and the mixture was stirred at rt.After 23.5 h another 0.08 mL (0.1 g, 1 mmol) methanesulfonyl chlorideadded, and the mixture was stirred for another 3.5 h. Another 0.1 mL(0.1 g, 1 mmol) methanesulfonyl chloride were added, and the mixture wasstirred for ca. another 1 h. Then the reaction was quenched with NH₄Cl(aq) and the mixture was extracted with dichloromethane thrice. Thecombined organic phases were dried (Na₂SO₄), filtered and concentrated.The crude product was purified by column chromatography (SiO₂, 0-50%ethyl acetate/hexane) to yield 775 mg (1.30 mmol, 84%) of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-((methylsulfonyl)oxy)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2) as a yellowish foam; MS (ESI) m/z 594.1 [M+1]⁺.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-cyano-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(3)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-((methylsulfonyl)oxy)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(2, 775 mg, 1.30 mmol) in DMSO (13 mL) was added potassium cyanide (189mg, 2.90 mmol) and the mixture was stirred at rt under argon. Afterstirring for 16 h the mixture was diluted with EtOAc and washed brine(2×), then dried (Na₂SO₄), filtered and concentrated. Purification bycolumn chromatography (SiO₂, 0-45% ethyl acetate/hexane) yielded 469 mg(0.892 mmol, 68%) of rac-methyl(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-cyano-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(3) as a yellowish foam; MS (ESI) m/z 525.2 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-cyano-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (4)

To rac-methyl(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-cyano-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(3, 460 mg, 0.875 mmol) in methanol (4.5 mL) and THF (4.5 mL) at rt wasadded LiOH (aq) (2M, 6.3 mL, 12.6 mmol) and the mixture was stirred at40° C. After 1 h the mixture was cooled down to rt, and stirred foranother 15 min, then acidified with 2M hydrochloric acid (aq) (7 mL) anddiluted with EtOAc and water. The aq. phase was extracted thrice, andthe combined organic phases were dried (Na₂SO₄), filtered andconcentrated to give 417 mg (0.815 mmol, 93%) ofrac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-cyano-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (4); MS (ESI) m/z 511.1 [M+1]⁺.

Synthesis ofrac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(5)

In a screw-cap vial,rac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-cyano-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylicacid (4, 387 mg, 0.756 mmol) and 1-hydroxypyridine-2-thione (144 mg,1.13 mmol) were suspended in Chloroform (7.5 mL).2-methylpropane-2-thiol (2.1 mL, 0.168 g, 18.6 mmol) was added, themixture was irradiated, and DCC (175 mg, 0.848 mmol) in 1.5 mL CHCl₃ wasadded dropwise under argon. The mixture was irradiated for 15 min withvigorous stirring without additional external heating. The mixture wasthen concentrated and dried in vacuo. Purification by repeated columnchromatography (first column: SiO₂, 0-25% ethyl acetate/hexane; secondcolumn: SiO₂, 0-20% ethyl acetate/hexane) yielded 136 mg (0.291 mmol,38%) ofrac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(5) as an off-white foam; MS (ESI) m/z 467.2 [M+1]⁺.

Synthesis ofrac-(5aR,6S,8R,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 174F)

To a solution ofrac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(5, 134. mg, 0.286 mmol) in THF (2.9 mL) at 0° C. was added LAH (27 mg,0.72 mmol) and the mixture was stirred at rt. After 30 min 0.1 mL waterwere added at 0° C., followed by 0.1 mL 12.5% NaOH (aq) and ca. 200 mgof Na₂SO₄. The mixture was stirred for 10 min at rt, then filteredthrough celite (rinsed with dichloromethane) and concentrated. The crudeproduct was taken up in 2 mL dichloromethane and treated withtrifluoroacetic acid (0.03 mL, 0.04 g, 0.4 mmol), then concentrated toyield 176 mg of crude TFA salt of (Cpd. No. 174F). Ca. 96 mg of thismaterial were used without purification for further derivatization. Therest was purified by HPLC (C18, MeCN/water+0.1% TFA), providing 22 mg ofpurerac-(5aR,6S,8R,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 174F) as the TFA salt as a white solid; MS (ESI) m/z 471.2[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (d, J=2.0 Hz, 1H), 7.84 (d,J=2.0 Hz, 1H), 7.81 (b, 3H), 7.33 (d, J=8.7 Hz, 2H), 7.15-7.05 (m, 5H),6.99-6.95 (m, 2H), 6.15 (s, 1H), 3.66 (dd, J=13.5, 6.4 Hz, 1H),3.44-3.35 (m, 1H), 3.22-3.13 (m, 1H), 2.86-2.76 (m, 1H), 2.38-2.24 (m,2H).

Example 175Rac-4-((5aR,6S,8R,8aR)-8-(aminomethyl)-3-chloro-8a-hydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 175F)

Synthesis ofrac-4-((5aR,6S,8R,8aR)-8-(aminomethyl)-3-chloro-8a-hydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 175F)

In a 0.5-2 mL microwave vialrac-(5aR,6S,8R,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(1, 48 mg, 0.082 mmol) was dissolved in N,N-dimethylformamide (0.7 mL)and water (0.07 mL). Zinc cyanide (39 mg, 0.33 mmol) and zinc (3 mg,0.05 mmol) were added, and the mixture was degassed by bubbling argonthrough it for 5 min. Dppf (14.0 mg, 0.0253 mmol) andTris(dibenzylideneacetone)dipalladium(0) (10.8 mg, 0.0118 mmol) wereadded and the mixture was degassed for another 5 min, then incubated at100° C. for 2.25 h in total. The mixture was filtered, diluted withMeCN, DMSO and water and subjected to purification by HPLC (C18MeCN/water+0.1% TFA) to provide 13.8 mg (32%) of the TFA salt ofrac-4-((5aR,6S,8R,8aR)-8-(aminomethyl)-3-chloro-8a-hydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 175F) as a white solid; MS (ESI) m/z 418.4 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 8.31 (d, J=2.0 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.82 (b,3H), 7.61 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H), 7.15-7.03 (m, 3H),6.99-6.94 (m, 2H), 6.22 (s, 1H), 3.74 (dd, J=13.7, 6.1 Hz, 1H),3.45-3.38 (m, 1H), 3.24-3.15 (m, 1H), 2.86-2.77 (m, 1H), 2.46-2.36 (m,1H), 2.36-2.23 (m, 1H).

Example 176Rac-(5aR,6S,8R,8aR)-8-(aminomethyl)-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-3-carbonitrile(Cpd. No. 176F)

Synthesis ofrac-(5aR,6S,8R,8aR)-8-(aminomethyl)-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-3-carbonitrile(Cpd. No. 176F)

In a 0.5-2 mL MW vialrac-(5aR,6S,8R,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(1, 48 mg, 0.08000 mmol) was dissolved in N,N-dimethylformamide (0.7 mL)and water (0.07 mL). Zinc cyanide (39 mg, 0.33 mmol) and zinc (3 mg,0.05 mmol) were added, and the mixture was degassed by bubbling argonthrough it for 5 min. Dppf (14.0 mg, 0.0253 mmol) andTris(dibenzylideneacetone)dipalladium(0) (10.8 mg, 0.0118 mmol) wereadded and the mixture was degassed for another 5 min, then incubated at140° C. for 1 h. Then the mixture was filtered, diluted with DMSO andMeCN, and directly subjected to purification by HPLC (C18,MeCN/water+0.1% TFA) to yield 3.6 mg (ca. 90% pure by ¹H-NMR, 8%) of theTFA salt ofrac-(5aR,6S,8R,8aR)-8-(aminomethyl)-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-3-carbonitrile(Cpd. No. 176F) as white solid; MS (ESI) m/z 409.2 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 8.75 (d, J=1.7 Hz, 1H), 8.21 (d, J=1.7 Hz, 1H), 7.86 (b,3H), 7.62 (d, J=8.7 Hz, 2H), 7.38 (d, J=8.7 Hz, 2H), 7.15-7.04 (m, 3H),6.98-6.94 (m, 2H), 6.39 (s, 1H), 3.75 (dd, J=14.0, 6.3 Hz, 1H),3.47-3.37 (m, 1H), 3.26-3.16 (m, 1H), 2.89-2.80 (m, 1H), 2.42 (b ddd,J=13, 13, 13 Hz, 1H), 2.34-2.26 (m, 1H).

Example 177Rac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 177F)

Synthesis ofrac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 177F)

To a solution ofrac-(5aR,6S,8R,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(1, 49 mg, 0.10 mmol) in N,N-dimethylformamide (0.7 mL) were addedN,N-Diisopropylethylamine (0.06 mL, 0.04 g, 0.3 mmol) and1-bromo-2-(2-bromoethoxy)ethane (15 mL, 28 mg, 0.12 mmol) and themixture was stirred at 80° C. After 1.5 h another 5 uLbis(bromoethyl)ether (9 mg, 0.04 mmol) were added at rt, and stirring at80° C. was continued for another 30 min. Then the mixture was cooled to0° C., diluted with water and treated with trifluoroacetic acid (0.04mL, 0.06 g, 0.5 mmol). The mixture was then diluted with MeCN andsubjected to HPLC purification (C18, MeCN/water+0.1% TFA) to yield 28.6mg (42%) ofrac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(Cpd. No. 177F) as its TFA salt, white solid; MS (ESI) m/z 541.2 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) d 9.33 (b, 1H), 8.31 (d, J=2.0 Hz, 1H), 7.85(d, J=2.0 Hz, 1H), 7.33 (d, J=8.8 Hz, 2H), 7.16-7.07 (m, 5H), 7.00-6.96(m, 2H), 6.21 (s, 1H), 4.09-3.97 (m, 2H), 3.84-3.28 (m, 8H, partiallyobscured by water peak), 3.25-3.13 (m, 1H), 3.12-3.01 (m, 1H), 2.44-2.32(m, 2H).

Example 178Rac-4-((5aR,6S,8R,8aR)-3-chloro-8a-hydroxy-8-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 178F)

Synthesis ofrac-4-((5aR,6S,8R,8aR)-3-chloro-8a-hydroxy-8-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 178F)

In a 0.5-2 mL microwave vialrac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol(1, 24 mg, 0.037 mmol) was dissolved in N,N-dimethylformamide (0.5 mL)and water (0.05 mL). Zinc cyanide (18.8 mg, 0.160 mmol) and zinc (1.3mg, 0.020 mmol) were added, and the mixture was degassed by bubblingargon through it for 5 min. Dppf (6.3 mg, 0.011 mmol) andTris(dibenzylideneacetone)dipalladium(0) (4.8 mg, 0.0053 mmol) wereadded and the mixture was degassed for another 5 min, then incubated at100° C. for 2 h in total. Then the mixture was filtered, diluted withMeCN, DMSO and water and subjected to purification by HPLC (C18,MeCN/water+0.1% TFA) to yield 10.6 mg (0.0176 mmol, 48%) ofrac-4-((5aR,6S,8R,8aR)-3-chloro-8a-hydroxy-8-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 178F) as TFA salt, white solid; MS (ESI) m/z 488.3 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) d 9.41 (b, 1H), 8.32 (d, J=2.0 Hz, 1H), 7.88 (d,J=2.0 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.6H, 2H), 7.15-7.04(m, 3H), 7.00-6.95 (m, 2H), 6.28 (s, 1H), 4.09-3.98 (m, 2H), 3.85-3.42(m, 7H, partially obscured by water peak), 3.42-3.30 (m, 1H), 3.25-3.14(m, 1H), 3.14-3.02 (m, 1H), 2.47-2.38 (m, 2H).

Example 179Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-(morpholinomethyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 179F)

Synthesis ofrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-(morpho-linomethyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol (Cpd. No.179F)

To a solution of cruderac-(4bR,5R,6R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 53. mg, 0.11000 mmol) in toluene (0.5 mL) and N,N-dimethylformamide(0.2 mL) at rt were added sodium bicarbonate (21 mg, 0.25 mmol) and1-bromo-2-(2-bromoethoxy)ethane (15 uL, 28 mg, 0.12 mmol) and themixture was stirred at 50° C. After 1 h partial product formationobserved and the mixture was warmed up to 70° C. After another 1 h themixture was warmed up to 90° C. After another 2 h at this temperaturethe mixture was allowed to cool to rt, then the reaction was quenchedwith NaHCO₃(aq). The mixture was extracted with dichloromethane (3×);and the organic phases were dried (Na₂SO₄), filtered and concentrated.The material was taken up in DMSO/MeCN/water for HPLC purification (C18,MeCN/water+0.1% TFA) to yield 7.9 mg (0.012 mmol, 11%) ofrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-(morpho-linomethyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 179F) as its TFA salt, white solid; MS (ESI) m/z 567.4 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (b, 1H), 8.19 (s, 1H), 8.15 (s, 1H),7.34 (d, J=8.5 Hz, 2H), 7.18-7.08 (m, 5H), 6.81-6.76 (m, 2H), 6.05 (s,1H), 4.18-4.07 (m, 1H), 4.03 (s, 3H), 3.93-3.83 (m, 1H), 3.82-3.11 (m,11H, partially obscured by water peak), 3.09 (d, J=13.4 Hz, 1H),2.97-2.86 (m, 1H).

Example 180Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-(morpholino-methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 180F)

Synthesis ofrac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-(morpholino-methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 180F)

In a 0.5-2 mL microwave vialrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-(morpholinomethyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 26 mg, 0.038 mmol) was dissolved in N,N-dimethylformamide (0.6 mL)and water (0.06 mL). Zinc cyanide (20 mg, 0.17 mmol) and zinc (1.5 mg,0.023 mmol) were added, and the mixture was degassed by bubbling argonthrough it for 5 min. Dppf (6.9 mg, 0.012 mmol) andTris(dibenzylideneacetone)dipalladium(0) (5.2 mg, 0.0057 mmol) wereadded and the mixture was degassed for another 5 min, then incubated at100° C. for 1.5 h in total. The mixture was filtered, diluted with MeCN,DMSO and water and subjected to purification by HPLC (C18,MeCN/water+0.1% TFA) to yield 6.1 mg (0.0097 mmol, 25%), of the TFA saltofrac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-(morpholino-methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 180F) as a white, hygroscopic solid; MS (ESI) m/z 514.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.02 (b, 1H), 8.21 (s, 1H), 8.16(s, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.39 (bd, 2H), 7.14-7.08 (m, 3H),6.81-6.76 (m, 2H), 6.12 (s, 1H), 4.20-4.07 (m, 1H), 4.04 (s, 3H),3.94-3.83 (m, 1H), 3.83-3.11 (m, 11H, partially obscured by water peak),3.15 (d, J=13.5 Hz, 1H), 3.04-2.94 (m, 1H).

Example 181Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-(((2,2-difluoroethyl)amino)methyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 181F)

Synthesis ofrac-N-(((4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-yl)methyl)-2,2-difluoroacetamide(2)

To a solution of cruderac-(4bR,5R,6R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 40 mg, 0.080 mmol) in methanol (0.8 mL) at rt were addedtriethylamine (24 mL, 17 mg, 0.17 mmol) and methyl 2,2-difluoroacetate(0.2 mL, 0.3 g, 2 mmol) and the mixture was stirred at rt. After 30 minthe mixture was concentrated in vacuo. The crude productrac-N-(((4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-yl)methyl)-2,2-difluoroacetamide(2) (MS (ESI) m/z 575.1 [M+1]⁺) was used without further purification.

Synthesis ofrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-(((2,2-difluoroethyl)amino)methyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta-[4,5]-furo-[2,3-c]pyridin-4b-ol(Cpd. No. 181F)

To a solution of cruderac-N-(((4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-yl)methyl)-2,2-difluoroacetamide(2, 12 mg, 0.021 mmol) in THF (0.4 mL) at 0° C. was added BH₃-DMScomplex in THF (0.07 mL, 0.14 mmol) and the mixture was stirred at 0° C.to 45 min, then at rt. After 2 h total reaction time warmed up to 40° C.and stirred for another 7 h, then over night at rt. 0.4 mL MeOH wereadded and the mixture was stirred at 60° C. for 3.5 h, then at 70° C.for 30 min. Then the mixture was concentrated, redissolved inMeCN/DMSO/water+a few drops of TFA and purified by HPLC (C18,MeCN/water+0.1% TFA) to yield 4.7 mg (0.0070 mmol, 33%) ofrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-(((2,2-difluoroethyl)amino)methyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta-[4,5]-furo-[2,3-c]pyridin-4b-ol(Cpd. No. 181F) as its TFA salt as a white solid; MS (ESI) m/z 561.2[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (b, 1H), 8.48 (b, 1H), 8.20 (s,1H), 8.14 (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 7.16-7.08 (m, 5H), 6.83-6.78(m, 2H), 6.57 (tt, J=53.8, 3.2 Hz, 1H), 6.37 (s, 1H), 5.57 (b, 1H), 4.00(s, 3H), 3.86-3.48 (m, 4H, partially obscured by water peak), 3.47-3.42(m, 1H), 3.26 (d, J=13.7 Hz, 1H), 3.20 (dd, J=11.1, 6.5 Hz, 1H),3.08-3.00 (m, 1H), 2.72-2.63 (m, 1H).

Example 182Rac-4-((4bR,5R,6R,7S,7aR)-5-(((2,2-difluoroethyl)amino)methyl)-4b-hydroxy-6-(hydroxyl-methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 182F)

Synthesis ofrac-4-((4bR,5R,6R,7S,7aR)-5-(((2,2-difluoroethyl)amino)methyl)-4b-hydroxy-6-(hydroxyl-methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 182F)

In a 0.5-2 mL microwave vialrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-(((2,2-difluoroethyl)amino)methyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 65 mg, 0.096 mmol) was dissolved in N,N-dimethylformamide (0.9 mL)and water (0.09 mL). Zinc cyanide (51 mg, 0.43 mmol) and zinc (3.1 mg,0.047 mmol) were added, and the mixture was degassed by bubbling argonthrough it for 5 min. Dppf (16 mg, 0.029 mmol) andTris(dibenzylideneacetone)dipalladium(0) (13 mg, 0.014 mmol) were addedand the mixture was degassed for another 5 min, then incubated at 100°C. for 2 h in total. The mixture was filtered, diluted with MeCN, DMSOand water and subjected to purification by HPLC (C18 MeCN/water+0.1%TFA) to yield 31 mg (93% pure, 48%) of the TAF salt ofrac-4-((4bR,5R,6R,7S,7aR)-5-(((2,2-difluoroethyl)amino)methyl)-4b-hydroxy-6-(hydroxyl-methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile)(Cpd. No. 182F) as a white solid. This material was 93% pure by ¹H-NMR(the major impurity appeared to be the reductive debromination product,i. e. H instead of CN in the 4′ position). A part of this material wasre-subjected to HPLC purification (C18, MeCN/water+0.1% TFA) to yieldmaterial of 95% purity; MS (ESI) m/z 508.4 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 9.58 (b, 1H), 8.55 (b, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.62(d, J=8.5 Hz, 2H), 7.37 (bd, J=8.5 Hz, 2H), 7.13-7.07 (m, 3H), 6.83-6.79(m, 2H), 6.57 (tt, J=53.6, 3.0 Hz, 1H), 6.43 (s, 1H), 5.64 (b, 1H), 4.01(s, 3H), 4.00-3.70 (m, 3H, partially obscured by water peak), 3.62-3.52(m, 1H), 3.46 (dd, J=11.1, 2.3 Hz, 1H), 3.33 (d, J=13.6 Hz, 1H), 3.21(dd, J=11.1, 6.7 Hz, 1H), 3.10-3.02 (m, 1H), 2.81-2.70 (m, 1H).

Example 183Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((4-methylpiperazin-1-yl)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 183F)

Synthesis ofrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((4-methylpiperazin-1-yl)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 183F)

To a solution ofrac-(4bR,5R,6R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 103 mg, 0.207 mmol) in ethanol (0.7 mL) at rt were added sodiumbicarbonate (97.5 mg, 1.16 mmol) and mechlorethamine hydrochloride (46mg, 0.24 mmol) and the mixture was stirred at 80° C. After 1 h Themixture was concentrated to approximately a third of its originalvolume, treated with 5 mL water, cooled down to 0° C., and acidifiedwith trifluoroacetic acid (0.14 mL, 0.21 g, 1.8 mmol), then diluted withMeCN/water and subjected to HPLC purification (C18, MeCN/water+0.1% TFA)to yield 41.3 mg (0.0595 mmol, 29%) of the TFA salt ofrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((4-methylpiperazin-1-yl)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 183F) as a white solid; MS (ESI) m/z 580.4 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 8.18 (s, 1H), 8.13 (s, 1H), 7.33 (d, J=8.7 Hz, 2H), 7.15(bd, J=8.7 Hz, 2H), 7.13-7.07 (m, 3H), 6.81-6.77 (m, 2H), 5.84 (b, 1H),4.00 (s, 3H), 3.53 (bd, J=11 Hz, 1H), 3.20 (bdd, J=11, 6 Hz, 1H), 3.18(d, J=13.7 Hz, 1H), 3.00-2.93 (m, 1H) [The remaining protons appeared asvery broad signals, partially obscured be the water peak, in the rangeof 4.1-2.6 pm].

Example 184Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-((4-methyl-piperazin-1-yl)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 184F)

Synthesis ofrac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-((4-methyl-piperazin-1-yl)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 184F)

In a 0.5-2 mL microwave vialrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((4-methylpiperazin-1-yl)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 36.6 mg, 0.0527 mmol) was dissolved in N,N-dimethylformamide (0.9mL) and water (0.09 mL). Zinc cyanide (29 mg, 0.25 mmol) and zinc (1.4mg, 0.021 mmol) were added, and the mixture was degassed by bubblingargon through it for 5 min. Dppf (8.8 mg, 0.016 mmol) andTris(dibenzylideneacetone)dipalladium(0) (7.2 mg, 0.0079 mmol) wereadded and the mixture was degassed for another 5 min, then incubated at100° C. for 2 h in total. The mixture was filtered, diluted with MeCN,DMSO and water, filtered again, and subjected to purification by HPLC(C18, MeCN/water+0.1% TFA) to yield 14.5 mg (0.0226 mol, 43%) of the TFAsalt ofrac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-((4-methyl-piperazin-1-yl)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 184F) as a white solid; MS (ESI) m/z 527.4 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 8.24 (s, 1H), 8.17 (s, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.39(bd, J=8.5 Hz, 2H), 7.13-7.04 (m, 3H), 6.83-6.76 (m, 2H), 4.02 (s, 3H),3.55 (dd, J=11.0, 2.5 Hz, 1H), 3.41-3.33 (m, 1H), 3.26-3.22 (m, 1H),3.23 (d, J=13.2 Hz, 1H), 3.08-3.00 (m, 1H), 2.88-2.77 (m, 1H), 2.83 (s,3H) [The remaining protons appeared as very broad signals in the rangesof 6.4-4.1 ppm and 3.83-2.77 ppm (partially obscured by the waterpeak)].

Example 185Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((oxetan-3-ylamino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 185F)

Synthesis ofrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((oxetan-3-ylamino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 185F)

To a suspension ofrac-(4bR,5R,6R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 50 mg, 0.10 mmol) in dichloromethane (1.5 mL) were addedoxetan-3-one (7.0 mL, 8.6 mg, 0.12 mmol), acetic acid (1.2 mL, 1.3 mg,0.021 mmol) and molecular sieves (ca. 60 mg). After 5 min THF (1 mL) wasadded for solubility reasons, and the mixture was stirred for another 25min. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) (STAB) was added.After 15 min another 0.03 mL (0.04 g, 0.6 mmol) 3-oxetanone were added.2 h after STAB addition virtually full conversion was observed by LCMS.The reaction was quenched by addition of NaHCO₃(aq) and brine andextracted (3× dichloromethane). The combined organic phases were dried(Na₂SO₄), filtered and concentrated. Purification by HPLC (C18,MeCN/water+0.1% TFA) yielded 32.8 mg (0.049 mmol, 49%) of the TFA saltofrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((oxetan-3-ylamino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 185F) as a white solid; MS (ESI) m/z 553.3 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 9.33 (b, 1H), 8.67 (b, 1H), 8.21 (s, 1H), 8.14 (s, 1H),7.34 (d, J=8.5 Hz, 2H), 7.15-7.07 (m, 5H), 6.81-6.77 (m, 2H), 6.29 (s,1H), 5.12 (b, 1H), 4.82-4.76 (m, 3H), 4.67 (dd, J=7.6, 5.8, 1H),4.62-4.53 (m, 1H), 4.00 (s, 3H), 3.62-3.49 (m, 1H), 3.51 (dd, J=11.4,2.8 Hz, 1H), 3.38-3.28 (m, 1H), 3.30 (d, J=13.6 Hz, 1H), 3.20 (dd,J=11.4, 5.8 Hz, 1H), 3.07-2.99 (m, 1H), 2.64-2.55 (m, 1H).

Example 186Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-((oxetan-3-ylamino)-methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)-benzonitrile(Cpd. No. 186F)

Synthesis ofrac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-((oxetan-3-ylamino)-methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)-benzonitrile(Cpd. No. 186F)

In a 0.5-2 mL microwave vialrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((oxetan-3-ylamino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 25 mg, 0.037 mmol) was dissolved in N,N-dimethylformamide (0.7 mL)and water (0.07 mL). Zinc cyanide (20.5 mg, 0.175 mmol) and zinc (1 mg,0.02 mmol) were added, and the mixture was degassed by bubbling argonthrough it for 5 min. Dppf (6 mg, 0.01 mmol) andTris(dibenzylideneacetone)dipalladium(0) (5 mg, 0.01 mmol) were addedand the mixture was degassed for another 5 min, then incubated at 100°C. for 2 h in total. The mixture was filtered, diluted with MeCN, DMSOand water, filtered again, and subjected to purification by HPLC (C18,MeCN/water+0.1% TFA) to yield 11.3 mg (0.0184 mmol, 49%) of the TFA saltofrac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-((oxetan-3-ylamino)-methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)-benzonitrile(Cpd. No. 186F) as a white solid; MS (ESI) m/z 500.3 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 9.45 (b, 1H), 8.83 (b, 1H), 8.23 (s, 1H), 8.16 (s, 1H),7.62 (d, J=8.4 Hz, 2H), 7.36 (bd, J=8.4 Hz, 2H), 7.13-7.06 (m, 3H),6.83-6.77 (m, 2H), 6.36 (s, 1H), 5.17 (b, 1H), 4.86-4.76 (m, 3H), 4.69(dd, J=7.7, 5.8 Hz, 1H), 4.63-4.54 (m, 1H), 4.00 (s, 3H), 3.64-3.54 (m,1H), 3.53 (dd, J=11.5, 2.8 Hz, 1H), 3.37 (d, J=13.6 Hz, 1H), 3.40-3.31(m, 1H), 3.22 (dd, J=11.5, 5.8 Hz, 1H), 3.10-3.00 (m, 1H), 2.75-2.64 (m,1H).

Example 187Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5-(((pyridin-4-ylmethyl)amino)methyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 187F)

Synthesis ofrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5-(((pyridin-4-ylmethyl)amino)methyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 187F)

To a solution ofrac-(4bR,5R,6R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 50 mg, 0.10 mmol) in THF (1 mL) were added pyridine-4-carbaldehyde(13 mL, 15 mg, 0.14 mmol), acetic acid (1.2 mL, 1.3 mg, 0.021 mmol) andmolecular sieves (ca. 80 mg). The mixture was stirred for 30 min. Sodiumtriacetoxyborohydride (85 mg, 0.40 mmol) was added. After 1 h thereaction was quenched with NaHCO₃ (aq), and the mixture was extracted(3× dichloromethane). The combined organic phases were dried (Na₂SO₄),filtered and concentrated. The crude product was taken up inMeCN/DMSO/water and subjected to purification by HPLC (C18,MeCN/water+0.1% TFA) to yield 52.6 mg (0.0749 mmol, 74%) of the TFA saltofrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5-(((pyridin-4-ylmethyl)amino)methyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 187F) as a white solid; MS (ESI) m/z 588.3 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 9.29 (b, 1H), 8.76-8.73 (m, 2H), 8.72 (b, 1H), 8.22 (s,1H), 8.14 (s, 1H), 7.66-7.63 (m, 2H), 7.32 (d, J=8.8 Hz, 2H), 7.14-7.04(m, 5H), 6.84-6.79 (m, 2H), 6.32 (s, 1H), 5.49 (b, 1H), 4.51-4.45 (m,2H), 3.91 (s, 3H), 3.75-3.61 (m, 1H), 3.50-3.41 (m, 1H), 3.44 (dd,J=11.2, 2.7 Hz, 1H), 3.26 (d, J=13.5 Hz, 1H), 3.21 (dd, J=11.2, 6.7 Hz,1H), 3.11-3.04 (m, 1H), 2.76-2.65 (m, 1H).

Example 188Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-5-(((pyridin-4-ylmethyl)amino)methyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 188F)

Synthesis ofrac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-5-(((pyridin-4-ylmethyl)amino)methyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 188F)

In a 0.5-2 mL microwave vialrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5-(((pyridin-4-ylmethyl)amino)methyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 39.7 mg, 0.0565 mmol) was dissolved in N,N-dimethylformamide (0.7mL) and water (0.07 mL). Zinc cyanide (32 mg, 0.27 mmol) and zinc (1.5mg, 0.023 mmol) were added, and the mixture was degassed by bubblingargon through it for 5 min. Dppf (9.4 mg, 0.017 mmol) andTris(dibenzylideneacetone)dipalladium(0) (7.5 mg, 0.0082 mmol) wereadded and the mixture was degassed for another 5 min, then incubated at100° C. for 2 h in total. The mixture was filtered, diluted with MeCN,DMSO and water, filtered again, and subjected to purification by HPLC(C18, MeCN/water+0.1% TFA) to affordrac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-5-(((pyridin-4-ylmethyl)amino)methyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 188F). Yield: 11.3 mg (0.0174 mmol, 31%); MS (ESI) m/z 535.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.31 (b, 1H), 8.80 (b, 1H),8.75-8.73 (m, 2H), 8.23 (s, 1H), 8.15 (s, 1H), 7.67-7.64 (m, 2H), 7.61(d, J=8.4 Hz, 2H), 7.34 (bd, J=8.4 Hz, 2H), 7.13-7.06 (m, 3H), 6.84-6.80(m, 2H), 6.37 (s, 1H), 5.58 (b, 1H), 4.52-4.45 (m, 2H), 3.91 (s, 3H),3.76-3.65 (m, 1H), 3.52-3.42 (m, 1H), 3.46 (dd, J=11.0, 2.4 Hz, 1H),3.33 (d, J=13.5 Hz, 1H), 3.23 (dd, J=11.0, 6.7 Hz, 1H), 3.12-3.05 (m,1H), 2.84-2.73 (m, 1H).

Example 189Rac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyridin-2-ylthio)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 189F)

Synthesis ofrac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyridin-2-ylthio)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 189F)

Rac-2-thioxopyridin-1(2H)-yl(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate(1, 34 mg, 0.060 mmol) was dissolved in dichloromethane (1.8 mL) in amicrowave vial. The vial was sealed then irradiated with 250 watthalogen lamp and the lamp and vial were enveloped in a sheet of aluminumfoil. After stirring under irradiating conditions overnight all solventhad evaporated. LCMS of this residue indicated that the thiopyridineproduct was the major component. This residue was purified by RP HPLC toaffordrac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyridin-2-ylthio)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile(Cpd. No. 189F). Yield: 17.9 mg, 57%; MS (ESI) m/z 514.2 (M+H) ¹H NMR(400 MHz, methanol-d₄) δ 8.53 (m, 1H), 8.17 (s, 1H), 7.73 (dd, 1H), 7.56(s, 1H). 7/52 (d, 2H), 7.43 (d, 2H), 7.41 (dd, 1H), 7.27 (dd, 1H),7.04-6.97 (m, 5H), 5.45 (m, 1H), 4.35 (d, 1H), 4.37 (d, 1H).

Example 190Rac-(5aR,6S,8aS)-5a-(4-bromophenyl)-3-chloro-8-ethynyl-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 190F)

Synthesis ofrac-(5aR,6S,8aS)-5a-(4-bromophenyl)-3-chloro-8-ethynyl-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 190F)

Rac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(1, 40.8 mg, 0.080 mmol) and flame dried lithium chloride (26 mg, 0.62mmol) were dissolved in THF (1 mL) in a flame dried vial. The mixturewas cooled to −10° C. and ethynyl magnesium bromide (0.97 mL 0.48 mmol)was added dropwise. The reaction was monitored by LCMS. After 1 hr thedesired product constituted a major component of reaction mixture. Thereaction was quenched after 1 hr at −10° C. with sat NH₄Cl, EtOAc wasadded, the layers separated and the aqueous layer was extracted withmore EtOAc ×2. The combined organic material was washed with brine anddried over magnesium sulfate. The mixture was purified by RP-HPLC toaffordrac-(5aR,6S,8aS)-5a-(4-bromophenyl)-3-chloro-8-ethynyl-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 190F). Yield: 33%; MS (ESI) m/z 553.3, 555.3 (M+H) ¹H NMR (400MHz, Chloroform-d) δ 8.13 (s, 1H), 7.44 (bs, 1H), 7.32 (s, 1H), 7.17 (d,J=8 Hz, 2H)), 7.09-7.03 (m, 5H), 2H), 6.91 (d, J=8 Hz, 2H), 4.86 (d,J=13.3 Hz, 1H), 4.48 (d, J=13.3 Hz, 1H), 3.44 (s, 3H), 3.02 (s, 3H),2.73 (s, 1H).

Example 191

Rac-(5aR,6S,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-8-(prop-1-yn-1-yl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 191F)

Synthesis ofrac-(5aR,6S,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-8-(prop-1-yn-1-yl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 191F)

Rac-(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-N,N-dimethyl-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(1, 39 mg, 0.060 mmol) and flame dried lithium chloride (21.3 mg, 0.5mmol) in THF (1 mL) to −10° C. 1-propynyl magnesium bromide (0.78 mL,0.39 mmol) was added dropwise. After 1 hr the desired productconstituted a major component of reaction mixture. The reaction wasquenched after 1 hr at −10° C. with sat NH₄Cl, EtOAc was added, thelayers separated and the aqueous layer was extracted with more EtOAc ×2.The combined organic material was washed with brine and dried overmagnesium sulfate. The mixture was purified by RP-HPLC to affordrac-(5aR,6S,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-8-(prop-1-yn-1-yl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide(Cpd. No. 191F) as a white solid. MS (ESI) m/z 567.1, 569.1 (M+H) ¹H NMR(400 MHz, DMSO-d₆) δ 8.13 (d, J=2.0 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H),7.14 (d, J=8 Hz, 2H), 7.10-7.00 (m, 4H), 6.96 (t, J=7.3 Hz, 1H),6.94-6.86 (m, 2H), 6.48 (s, 1H), 6.22 (s, 1H), 5.40 (s, 1H), 4.71 (d,J=13.2 Hz, 1H), 4.48 (d, J=13.3 Hz, 1H), 3.43 (s, 3H), 2.86 (s, 3H),1.89 (s, 3H).

Example 192Rac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-N,N-dimethyl-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 192F)

Synthesis ofrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-N,N-dimethyl-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 192F)

Rac-methyl(4bR,6R,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(1, 250 mg, 0.49 mmol) and potassium carbonate (1.596 g, 4.9 mmol) wereplaced in vial and then DMSO (5 mL) was added. Dimethylaminehydrochloride salt (0.04 mL) 1.47 mmol) was added to the solution andthe mixture heated to 130° C. After 5 hr LCMS indicated full consumptionof the starting material. The pot was cooled to rt and the solution wasdissolved in EtOAc and sat. aq. NH₄Cl. The layers were separated andaqueous material extracted with EtOAc ×3; the combined organic materialwas washed with brine and dried over magnesium sulfate. Purification byautomated flash chromatography (eluting twice dichloromethane and MeOH)led to isolation of product in good purity. A small portion was furtherpurified by semiprep RP-HPLC to affordrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-N,N-dimethyl-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 192F) as a white solid. MS (ESI) m/z 523.1, 525.1 (M+H) ¹H NMR(400 MHz, DMSO-d₆) δ 8.30 (d, J=0.4 Hz, 1H), 8.12 (d, J=0.4 Hz, 1H),7.33 (d, J=8 Hz, 2H), 7.14-7.01 (m, 5H), 6.97-6.90 (m, 2H), 6.59 (s,1H), 4.72 (d, J=13.2 Hz, 1H), 4.18 (d, J=13.2 Hz, 1H), 3.86 (s, 3H),2.74 (s, 3H).

Example 193 Rac-Methyl(4bS,5R,6R,7aR)-4b,5-dihydroxy-7a-(4-iodophenyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(Cpd. No. 193F)

Synthesis of rac-methyl(4bS,5R,6R,7aR)-4b,5-dihydroxy-7a-(4-iodophenyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(Cpd. No. 193F)

Cyclohexane-1,2-diamine (11. mg, 0.10000 mmol) was placed in a vial withNMP (1 mL). Sodium iodide (52.66 mg, 0.35 mmol) and rac-methyl(4bS,5R,6R,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(1, 90. mg, 0.18000 mmol) were added, followed by copper(I) iodide(10.04 mg, 0.05000 mmol). The mixture was degassed by sparging with anargon balloon for 10 min. The vial was sealed and heated to 120° C. Thereaction was monitored by LCMS. After heating for 23 hr the reaction wascooled to rt and diluted with 10 mL dichloromethane and filtered throughcelite. The filtrate was rotavapped and then the residue was taken up inEtOAc. Saturated aq NH₄Cl was added, the layers separated and aqueouslayer extracted with EtOAc ×3. The combined organic material was washedwith brine and dried over magnesium sulfate. In order to remove anyresidual copper the residue was taken up in EtOAc. Water and 1 mL 3M NH₃in dioxane were added and the aqueous layer was extracted with EtOAc ×3.The combined organic material was washed with brine and dried overmagnesium sulfate. The crude material was purified on semiprep RP-HPLCto afford rac-methyl(4bS,5R,6R,7aR)-4b,5-dihydroxy-7a-(4-iodophenyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(Cpd. No. 193F) as a white solid. Yield 43%; MS (ESI) m/z 560.2 (M+H) ¹HNMR (400 MHz, DMSO-d₆) δ 8.19 (s, 1H), 8.04 (s, 1H), 7.34 (d, J=8 Hz,2H), 7.08-6.99 (m, 2H), 7.01-6.90 (m, 3H), 6.87 (d, J=8 Hz, 2H), 5.84(s, 1H), 5.67 (s, 1H), 4.67 (d, J=4.8 Hz, 1H), 4.30 (d, J=13.9 Hz, 1H),4.07 (dd, J=14.0, 4.9 Hz, 1H), 3.86 (d, J=1.1 Hz, 3H), 1.21 (s, 1H).

Example 194Rac-4-((4bS,5R,6S,7S,7aR)-6-((4-acetylpiperazin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 194F)

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-6-((4-acetylpiperazin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 194F)

Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(piperazin-1-ylmethyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(1, 25 mg, 0.05 mmol) was dissolved in dichloromethane (0.5 mL) in amicrowave vial. Triethylamine (0.03 mL, 0.2 mL) was then added, followedby acetic anhydride (0.01 mL, 0.06 mmol). The vial was sealed andstirred at rt. LCMS at 30 min indicated complete conversion to product.The reaction mixture was poured onto saturated aqueous NaHCO₃ anddiluted with dichloromethane. The aqueous layer was extracted withdichloromethane ×3, the combined organic material was washed with brineand dried over magnesium sulfate. The crude material was purified byRP-HPLC to affordrac-4-((4bS,5R,6S,7S,7aR)-6-((4-acetylpiperazin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 194F) as a fluffy white solid after lyophilization. Yield 59%;MS (ESI) m/z 494.0, 496.0 (M+H) ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s,1H), 8.08 (dd, J=28, 2.7 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.40 (d, J=8.5Hz, 1H), 7.13-6.95 (m, 3H), 5.90 (bs, 1H), 5.45 (bs, 1H), 4.72 (bs, 1H),4.44 (bs, 1H), 3.98 (bs, 1H), 3.89 (d, J=0.7 Hz, 3H), 3.85-3.72 (m, 2H),3.85-3.72 (m, 2H), 3.29 (m, 1H), 3.07-2.9 (m, 3H), 2.02 (d, J=8.3 Hz,2H).

Example 195Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 195F)

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-N-(2,2-difluoroethyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(2)

Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 80 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (3mLin a vial under argon. Added HATU (60 mg, 0.16 mmol) After 30 minDIPEA (0.08 mL, 0.45 mmol) was added with automated pipette and thesolution stirred at rt 45 min then 2,2 difluoroethylamine hydrochloridesalt (0.45 mmol) was added in one portion. LCMS at 3 hr looks like >90%conversion to product. The reaction mixture was diluted with 90%EtOAc:Hexanes and washed with water 3×, then brine and dried overmagnesium sulfate. The crude product was purified by automated flashchromatography to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-N-(2,2-difluoroethyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(2) as a white solid, which was carried on to the next step. MS (ESI)m/z 593.2, 595.2 (M+H).

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 195F)

Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-N-(2,2-difluoroethyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(2, 96 mg, 1.6 mmol) was stirred in THF (3 mL) under argon. Boranedimethylsulfide complex (0.15 mL, 1.59 mmol) was added dropwise andsubsequently attached a reflux condenser and warmed to 35° C. LCMS of analiquot at 5 hours looks like almost all SM has been consumed, so thereaction was quenched very slowly with 2 mL MeOH. It was then heated to60° C. for 3 hr then cooled to rt overnight (14 hr) and then heated anadditional 6 hr at 60° C. at which time LCMS looks like full conversionto product. Solvent was rotavapped and purification was carried out withphenomonex ion exchange column: the column was wetted with water, thenthe crude residue was loaded as a solution in DMSO/MeCN. The column waswashed 2× each with Water, MeCN, and Methanol, and the product waseluted with a 75:20:5 MeOH:dichloromethane:NH4OH solution (column washedwith this solution ×3. these combined washes were rotavapped and theproductrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 195F) was isolated with high purity as a white solid. Yield:82.6 mg, 82% (over 2 steps); MS (ESI) m/z 581.2, 583.1 (M+H) ¹H NMR (400MHz, DMSO-d₆) δ 7.29-7.15 (m, 3H), 7.11-6.90 (m, 10H), 6.84 (s, 1H),5.93 (t, J=4.3 Hz, 1H), 5.50 (s, 1H), 5.15 (d, J=5.5 Hz, 1H), 4.44 (t,J=4.9 Hz, 1H), 3.82 (s, 4H), 3.63 (d, J=14.3 Hz, 1H), 3.06 (s, 2H), 3.05(dd, J=14.0, 10.1 Hz, 0H), 2.83 (t, J=16.1 Hz, 3H), 2.63 (t, J=10.8 Hz,2H), 1.20 (s, 1H).

Example 196Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 196F)

Synthesis ofrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 196F)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 27 mg, 0.046 mmol) was dissolved in in N,N-dimethylformamide (0.60mL) and water (0.060 mL) and the solution was sparged with argon for 10minutes. Zinc cyanide (33 mg, 0.278 mmol), zinc (3.0 mg, 0.0464 mmol),Tris(dibenzylideneacetone)dipalladium(0) (3.3 mg, 0.0037 mmol), and dppf(4.1 mg 0.0074 mmol) were added and the mixture heated at 110° C. for 2hours, at which point LCMS modest conversion to product. The mixture wasimmediately cooled to rt, filtered through celite, and the filtrate waspurified by RP-HPLC to affordrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 196F) as a fluffy white solid. Yield 10%; LCMS (ESI) m/z528.2, 530.3 (M+H)¹H NMR (400 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.94 (s,1H), 7.55 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.5 Hz, 2H), 7.14-6.98 (m, 2H),7.00-6.90 (m, 2H), 6.37 (t, J=48 Hz, 1H), 5.78 (s, 1H), 5.28 (d, J=6.2Hz, 1H), 4.63 (s, 1H), 3.84 (s, 2H), 3.76 (d, J=14.1 Hz, 1H), 3.55 (bs,1H), 3.12 (bs, 1H), 2.94 (bs, 1H), 2.81 (bs, 1H).

Example 197Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 197F)

Synthesis of rac-tert-butyl(((5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)methyl)(2,2-difluoroethyl)carbamate(2)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 20.2 mg, 0.029 mmol, 1 eq.) was stirred in dichloromethane (0.6 mL)and N,N-dimethylformamide (0.7 mL). Triethylamine (0.012 mL, 0.085 mmol)was added, followed by di-tert-butyl dicarbonate (10.0 mg, 0.0458 mmol)and the mixture stirred at rt fir 40 and subsequently warmed to 35° C.for 8 hr, at which point complete consumption of starting material wasobserved by LCMS. The solvent was removed in vacuo and the residue waspurified by flash chromatography eluting with hexanes and ethyl acetateto afford rac-tert-butyl(((5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)methyl)(2,2-difluoroethyl)carbamate(2) as a white residue that was carried on to the next step. LCMS (ESI)m/z 681.3, 683.4 (M+H)

Synthesis of rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 197F)

Rac-tert-butyl(((5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)methyl)(2,2-difluoroethyl)carbamate(2, 21 mg, 0.03000 mmol) was dissolved in N,N-dimethylformamide (0.70mL) and water (0.070 mL). Zinc dust (2.0 mg), zinc cyanide (23.5 mg,0.2006 mmol) Tris(dibenzylideneacetone)dipalladium(0) (1.7 mg, 0.00185mmol), and dppf (2.05 mg, 0.0037 mmol) were added and the mixturesparged with argon for 5 min. The vial was sealed and then heated to120° C. for 40 min and then cooled to rt. LCMS-rapid conversion toproduct and moncyano compound (ca 9:1 product:monocyano after 20 min).After 40 minutes the reaction mixture was diluted with 2.5 mLdichloromethane and filtered with syrringe filter. TFA (0.03 mL) wasadded and the mixture stirred at rt for 1 hr then at 40° C. for 18 hr.The reaction was cooled to rt and passed through an ion exchange column,eluting with water, MeCN, and MeOH, (3× each) and then the produce waswashed off column with a 75:20:5 solution of MeOH:dichloromethane:NH₄OH.The material was further purified by RP-HPLC to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 197F). Yield: 25%; LCMS (ESI) m/z 519.3 (M+H) 1H NMR (400 MHz,DMSO-d₆) δ 9.04 (s, 1H), 7.56 (d, J=8.9 Hz, 2H), 7.29 (d, J=8.5 Hz, 1H),7.13-6.95 (m, 4H), 6.38, t, J=52 Hz, 1H), 5.94 (s, 1H), 5.43 (s, 1H),4.69 (s, 1H), 3.89 (s, 2H), 3.76 (d, J=14.2 Hz, 1H), 3.64-3.54 (bs, 3H),3.50-3.21 (bs, 3H), 3.10 (s, 1H), 2.84 (bs, 1H).

Example 1984-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 198aF)Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 198bF)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(2)

Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1) was dissolved in N,N-dimethylformamide (2.8 mL) under anatmosphere of argon. HATU (124 mg, 0.33 mmol) was added in one portionand 2 minutes later Hunig's base (0.08 mmol, 0.45 mmol) was addeddropwise. After 20 min LCMS (taken in MeOH) looks like completeconsumption of (1). 1-methylpiperizine (0.1 mL, 0.93 mmol) was added andthe reaction mixture stirred another 40 min, at which time LCMS showscomplete conversion to product. The reaction mixture was cooled, pouredonto water, diluted with 90% EtOAc/hexanes, and the organic material waswashed an additional 3× with water. It was then washed with brine anddried over magnesium sulfate. The product was purified by flashchromatography to provide a solid of sufficient purity for the nextstep.

The intermediate amide was dissolved in THF (3 mL) and a solution ofborane dimethyl sulfide complex (0.151 mL, 1.59 mmol) was added dropwiseand the mixture subsequently warmed to 35° C. under a reflux condenser.LCMS of an aliquot at 5 hours looks like almost all starting materialhas been consumed, so the reaction was quenched very slowly with 2 mL ofmethanol. It was then heated to 60° C. for 3 hr then cooled to roomtemperature and stirred overnight (14 hr) and then heated an additional6 hr at 60° C. at which time LCMS looks like full conversion to product.Solvent was rotavapped and purification was carried out with phenomonexion exchange column: the column was wetted with water, then the cruderesidue was loaded as a solution in DMSO/MeCN. The column was washed 2×each with Water, MeCN, and Methanol, and the product was eluted with a75:20:5 MeOH:dichloromethane:NH₄OH solution (column washed with thissolution ×3. these combined washes were rotavapped and the product wasisolated with high purity.

Synthesis of4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 198aF)Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 198bF)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(2, 28 mg, 0.046 mmol) was dissolved in N,N-dimethylformamide (0.80 mL)and water (0.080 mL) and the solution was sparged with argon for 10minutes. Zinc cyanide (35 mg, 0.30 mol), zinc dust (3 mg, 0.047 mmol),Tris(dibenzylideneacetone)dipalladium(0) (2.6 mg, 0.003 mmol), and dppf(3 mg, 0.005 mmol) were added and the mixture heated at 110° C. for 30minutes, at which point LCMS indicated conversion to a mixture ofstarting material, mono- and bis-cyanated compounds. The mixture wasimmediately cooled to rt, filtered through celite, and the filtrate waspurified by RP-HPLC to afford the both mono- and bis-cyanated productsas white solids. Combined yield 11%

4-((5aR,6S,7S,8R,8aS)-3-Chloro-8,8a-dihydroxy-1-methoxy-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile:The enantiomers were separated by chiral SFC [CHIRALPAK IG (4.6×250)mm,5μ], Mobile Phase: CO₂/MeOH/TEA(60:40:0.2)], Peak 1 (1.56 g),R_(t)=2.833 min, ee: 99.92%, [α]_(D) +47.1° (c 0.25, CHCl₃); MS (ESI)m/z 547.24[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 7.49 (d, J=8.52 Hz, 2H),7.34 (d, J=8.48 Hz, 2H), 7.08-7.05 (m, 2H), 7.00-6.97 (m, 3H), 6.88 (s,1H), 5.66 (s, 1H), 5.14 (bs, 1H), 4.42 (d, J=3.72 Hz, 1H), 3.84 (s, 3H),3.77 (d, J=14.04 Hz, 1H), 3.22-3.20 (m, 1H), 2.62-2.56 (m, 2H),2.49-2.32 (m, 7H), 2.15 (s, 3H), 2.05 (d, J=9.92 Hz, 1H); Peak-2 (Cpd.No. 198aF, 1.55 g), R_(t)=3.83 min, ee: 99.36%, [α] _(D) −29.2° (c 0.30,CHCl₃); MS (ESI) m/z 547.24[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 7.49 (d,J=8.52 Hz, 2H), 7.34 (d, J=8.48 Hz, 2H), 7.08-7.05 (m, 2H), 7.00-6.97(m, 3H), 6.88 (s, 1H), 5.66 (s, 1H), 5.15 (bs, 1H), 4.43 (bs, 1H), 3.84(s, 3H), 3.77 (d, J=14.12, Hz, 1H), 3.22-3.20 (m, 1H), 2.62-2.56 (m,2H), 2.49-2.32 (m, 7H), 2.15 (s, 3H), 2.05 (d, J=9.92 Hz, 1H).

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 198bF): MS (ESI) m/z 538.7 (M+H) ¹H NMR (400 MHz, DMSO-d₆) δ7.54 (s, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.07-6.95(m, 5H) 5.81 (s, 1H), 4.48 (s, 1H), 3.87 (s, 3H), 3.73 (d, J=14.1 Hz,1H), 2.96 (bs, 5H), 2.77 (bs, 3H).

Example 199Rac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-1-methoxy-8-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(Cpd. No. 199F)

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-1-methoxy-8-((methylsulfonyl)oxy)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(2)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-7,8-dihydro-6H-cyclopenta[4,5]furo[1,2-d]pyridine-7-carboxylate(1, 20 mg, 0.037 mmol) in pyridine (0.40 mL) was added methanesulfonylchloride (4 mL, 6 mg, 0.05 mmol) and the mixture was stirred at rtovernight. After 18 h another 2 mL (3 mg, 0.03 mmol) methanesulfonylchloride were added, followed by another 3 mL (4 mg, 0.04 mmol)methanesulfonyl chloride. After 2 days total reaction time the reactionwas quenched with NH₄Cl(aq) and the mixture was extracted withdichloromethane thrice. The combined organic phases were dried (Na₂SO₄),filtered and concentrated to afford rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-1-methoxy-8-((methylsulfonyl)oxy)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(2). The crude product [MS (ESI) m/z 624.2 [M+1]⁺] was used withoutfurther purification in the next step.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-cyano-8a-hydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(3)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-1-methoxy-8-((methylsulfonyl)oxy)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(2, 22.9 mg, 0.0367 mmol) in DMSO (0.50 mL) was added potassium cyanide(5.3 mg, 0.082 mmol) and the mixture was stirred at rt under argon.After 17 h the mixture was diluted with EtOAc and washed brine. The aq.phase was re-extracted with EtOAc, and the combined organic phases weredried (Na₂SO₄), filtered and concentrated. Purification by columnchromatography (SiO₂, 0-35% ethyl acetate/hexane) provided the desiredproduct rac-methyl(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-cyano-8a-hydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(3) as a white foam. Yield: 15.9 mg (0.0286 mmol, 77% over 2 steps); MS(ESI) m/z 555.2 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol (4)

To a solution of rac-methyl(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-cyano-8a-hydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(3, 15.9 mg, 0.0286 mmol) in THF (0.50 mL) at 0° C. was added lithiumaluminum hydride (4.3 mg, 0.11 mmol) and the mixture was stirred at rt.After 45 min 0.02 mL water were added at 0° C., followed by 0.02 mL12.5% NaOH (aq) and ca. 50 mg of Na₂SO₄. The mixture was stirred for 10min at rt, then filtered (rinsed with THF and dichloromethane) andconcentrated to give 15.8 mg of the crude desired amino alcohol ofrac-(5aR,6S,7R,8R,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(4) as a white solid; MS (ESI) m/z 531.2 [M+1]⁺. The crude material wasused in the next step without further purification.

Synthesis ofrac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-1-methoxy-8-(morpholinomethyl)-6-phenyl-5a,6,7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol (Cpd. No.199F)

To a solution of cruderac-(5aR,6S,7R,8R,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(4, 15.8 mg) in N,N-dimethylformamide (0.50 mL) were addedN,N-diisopropylethylamine (18 mL, 13 mg, 0.10 mmol) and1-bromo-2-(2-bromoethoxy)ethane (4.5 mL, 8.3 mg, 0.036 mmol) and themixture was stirred at 80° C. After 1 h 45 min and 2.5 h another 1.5 mL(2.8 mg, 0.012 mmol) bis(bromoethyl)ether were added, and stirring at80° C. was continued. After 3.75 h total reaction time the mixture wasallowed to cool down to rt, then diluted with MeCN/DMSO/water andacidified with trifluoroacetic acid (20 mL, 30 mg, 0.26 mmol). The soobtained mixture was subjected to repeated HPLC purification (C18,MeCN/water+0.1% TFA) to provide the desired productrac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-1-methoxy-8-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(Cpd. No. 199F) as its TFA salt. Yield: 2.5 mg (0.0035 mmol, 12% over 2steps), white solid; MS (ESI) m/z 601.4 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 9.91 (b, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.16-7.06 (m, 5H), 7.03(s, 1H), 6.82-6.74 (m, 2H), 5.95 (s, 1H), 4.21-4.06 (m, 1H), 3.99 (s,3H), 3.90-3.19 (m, 12H; partially obscured by water peak), 3.17-3.10 (m,1H), 3.14 (d, J=13.6 Hz, 1H), 2.94-2.84 (m, 1H).

Example 200Rac-(5aR,6S,7R,8R,8aR)-5a-(4-cyanophenyl)-8a-hydroxy-7-(hydroxymethyl)-1-methoxy-8-(morpholinomethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 200F)

Synthesis ofrac-(5aR,6S,7R,8R,8aR)-5a-(4-cyanophenyl)-8a-hydroxy-7-(hydroxymethyl)-1-methoxy-8-(morpholinomethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 200F)

In a vial,rac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-1-methoxy-8-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(1, 29.4 mg, 0.0411 mmol) was dissolved in N,N-dimethylformamide (0.40mL) and water (0.04 mL), and zinc (0.8 mg, 0.01 mmol) and zinc cyanide(24.5 mg, 0.209 mmol) were added. The mixture was degassed by bubblingargon through it for 5 min. Then dppf (6.8 mg, 0.012 mmol) and Pd₂dba₃(5.6 mg, 0.0062 mmol) were added. The mixture was degassed by bubblingargon through it for another 5 min, then the vial was sealed and placedin a preheated heating block (110° C.). The mixture was stirred for 2 h.Then the mixture was filtered, diluted with MeCN, DMSO and water, andfiltered again. The filtrate and the precipitate were separatelysubjected to HPLC purification (C18, MeCN/water+0.1% TFA) to afford theTFA salt of the desired productrac-(5aR,6S,7R,8R,8aR)-5a-(4-cyanophenyl)-8a-hydroxy-7-(hydroxymethyl)-1-methoxy-8-(morpholinomethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 200F) as a white solid. Yield: 7.0 mg, 26%; MS (ESI) m/z 539.4[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (b, 1H), 7.72 (s, 1H), 7.65(bd, 2H), 7.36 (b, 2H), 7.15-7.06 (m, 3H), 6.82□6.75 (m, 2H), 6.17 (s,1H), 4.23-4.02 (m, 1H), 4.05 (s, 3H), 3.88-3.79 (m, 1H), 3.79-3.24 (m,11H; partially obscured by water peak), 3.22-3.15 (m, 1H), 3.19 (d,J=13.6 Hz, 1H), 3.04-2.93 (m, 1H).

Example 201Rac-(4bR,5R,6R,7S,7aR)-5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 201F)

Synthesis of rac-(4bR,5R, 6R,7S,7aR)-5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 201F)

To a solution ofrac-(5aR,6S,7R,8R,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-7-(hydroxyl-methyl)-1-methoxy-6-phenyl-7,8-dihydro-6H-cyclopenta[4,5]furo[1,2-b]pyridin-8a-ol(1, 51 mg, 0.10 mmol) in N,N-dimethylformamide (0.60 mL) were addedN,N-diisopropylethylamine (0.060 mL, 45 mg, 0.34 mmol) and3,3-bis(bromomethyl)oxetane (17 □L, 32 mg, 0.13 mmol) in 0.2 mLN,N-dimethylformamide and the mixture was stirred at 80° C. After 3 hanother 6 μL (0.01 g, 0.05 mmol) bis(bromoethyl)oxetane were added.After another 1 h another 3 μL (6 mg, 0.02 mmol) bis(bromoethyl)oxetanewere added. After another 30 min the mixture was allowed to cool down tort, then diluted with MeCN/water and acidified with trifluoroacetic acid(0.08 mL, 0.1 g, 1 mmol). Purification by HPLC (C18, MeCN/water+0.1%TFA) provided the TFA salt ofrac-(4bR,5R,6R,7S,7aR)-5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 201F) as a white solid. Yield: 31.8 mg, 45%; MS (ESI) m/z579.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (b, 1H), 8.21 (s, 1H),8.17 (s, 1H), 7.35 (d, J=8.7 Hz, 2H), 7.13-7.06 (m, 5H), 6.81-6.76 (m,2H), 6.24 (s, 1H), 5.12 (b, 1H), 4.83 (d, J=7.1 Hz, 1H), 4.76 (d, J=7.1Hz, 1H), 4.73-4.69 (m, 2H), 4.61-4.50 (m, 2H), 4.40 (dd, J=11.0, 5.8 Hz,1H), 4.21 (dd, J=11.0, 5.8 Hz, 1H). 4.07 (s, 3H), 3.89-3.81 (m, 1H),3.60-3.51 (m, 1H), 3.49 (dd, J=11.4, 2.6 Hz, 1H), 3.26 (d, J=13.4 Hz,1H), 3.16 (dd, J=11.4 Hz, 5.1 Hz, 1H), 2.95-2.88 (m, 1H), 2.51-2.42 (m,1H).

Example 202Rac-4-((4bR,5R,6R,7S,7aR)-5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 202F)

Synthesis of rac-4-((4bR,5R, 6R,7S,7aR)-5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 202F)

In microwave vialrac-(4bR,5R,6R,7S,7aR)-5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 24.5 mg, 0.0353 mmol) was dissolved in N,N-dimethylformamide (0.70mL) and Water (0.07 mL). Zinc cyanide (21 mg, 0.18 mmol) and zinc (0.9mg, 0.01 mmol) were added, and the mixture was degassed by bubblingargon through it for 5 min. Dppf (5.7 mg, 0.010 mmol) andtris(dibenzylideneacetone)dipalladium(0) (4.7 mg, 0.0052 mmol) wereadded and the mixture was degassed for another 5 min, then incubated at100° C. for 2 h in total. The mixture was filtered, diluted with MeCN,DMSO and water, filtered again, and subjected to purification by HPLC(C18, MeCN/water+0.1% TFA) to provide compoundrac-4-((4bR,5R,6R,7S,7aR)-5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 202F) as the corresponding TFA salt. Yield: 7.4 mg, 33%, whitesolid; MS (ESI) m/z 526.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (b,1H), 8.23 (s, 1H), 8.18 (s, 1H), 7.62 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.7Hz, 2H), 7.13-7.05 (m, 3H), 6.82-6.74 (m, 2H), 6.32 (s, 1H), 5.20 (b,1H), 4.83 (d, J=7.2 Hz, 1H), 4.76 (d, J=7.2 Hz, 1H), 4.74-4.68 (m, 2H),4.61-4.51 (m, 2H), 4.42 (dd, J=11.1, 5.8 Hz, 1H), 4.21 (dd, J=10.7, 5.4Hz, 1H), 4.07 (s, 3H), 3.92-3.84 (m, 1H), 3.62-3.55 (m, 1H), 3.50 (dd,J=11.5, 2.7 Hz, 1H), 3.32 (d, J=13.6 Hz, 1H), 3.16 (dd, J=11.5, 5.4 Hz,1H), 2.97-2.89 (m, 1H), 2.60-2.50 (m, 1H).

Example 203Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 203F)

Synthesis ofrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 203F)

To a solution ofrac-(4bR,5R,6R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 50 mg, 0.10 mmol) in THF (1 mL) were added2-methylpyrazole-3-carbaldehyde (12 μL, 13 mg, 0.12 mmol), acetic acid(1.2 μL, 1.3 mg, 0.021 mmol) and molecular sieves (ca. 80 mg). Themixture was stirred for 30 min. Then sodium triacetoxyborohydride (85mg, 0.40 mmol) was added, and the mixture was stirred for 30 min.Another 3 μL (3 mg, 0.03 mmol) 2-methylpyrazole-3-carbaldehyde wereadded. After another 30 min the reaction was quenched with NaHCO₃(aq),and the mixture was extracted (3× dichloromethane). The combined organicphases were dried (Na₂SO₄), filtered and concentrated. The crude productwas taken up in MeCN/DMSO/water. And subjected to HPLC purification(C18, MeCN/H₂O+0.1% TFA) to provide productrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 203F) as its TFA salt. Yield: 40.5 mg (0.0574 mmol, 57%),white solid; MS (ESI) m/z 591.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.14(b, 1H), 8.52 (b, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 7.52 (d, J=1.9 Hz,1H), 7.34 (d, J=8.6 Hz, 2H), 7.14-7.08 (m, 5H), 6.85-6.80 (m, 2H), 6.53(d, J=1.9 Hz, 1H), 6.35 (s, 1H), 5.52 (b, 1H), 4.63-4.48 (m, 2H), 3.92(s, 3H), 3.91 (s, 3H), 3.78-3.68 (m, 1H), 3.54-3.44 (m, 1H), 3.45 (dd,J=11.1, 2.5 Hz, 1H), 3.27 (d, J=13.6 Hz, 1H), 3.21 (dd, J=11.4, 6.8 Hz,1H), 3.10-3.02 (m, 1H), 2.76-2.66 (m, 1H).

Example 204Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 204F)

Synthesis ofrac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 204F)

In a microwave vialrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 29.7 mg, 0.0421 mmol) was dissolved in N,N-dimethylformamide (0.70mL) and water (0.07 mL). Zinc cyanide (25 mg, 0.21 mmol) and zinc (1 mg,0.02 mmol) were added, and the mixture was degassed by bubbling argonthrough it for 5 min. Dppf (6.6 mg, 0.012 mmol) andTris(dibenzylideneacetone)dipalladium(0) (5.5 mg, 0.0060 mmol) wereadded and the mixture was degassed for another 5 min, then incubated at100° C. for 2 h in total. The mixture was filtered, diluted with MeCN,DMSO and water, filtered again, and subjected to purification by HPLC(C18, MeCN/water+0.1% TFA) to provide compoundrac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 204F) as its TFA salt. Yield: 13.3 mg, 48%, white solid; MS(ESI) m/z 538.6 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (b, 1H), 8.66(b, 1H), 8.24 (s, 1H), 8.15 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.52 (d,J=1.9 Hz, 1H), 7.36 (bd, J=8.4 Hz, 2H), 7.13-7.04 (m, 3H), 6.85-6.79 (m,2H), 6.53 (d, J=1.9 Hz, 1H), 6.41 (s, 1H), 5.59 (b, 1H), 4.64-4.47 (m,2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.83-3.70 (m, 1H), 3.57-3.47 (m, 1H),3.47 (dd, J=11.2, 2.6, 1H), 3.34 (d, J=13.5 Hz, 1H), 3.22 (dd, J=11.2,6.6 Hz, 1H), 3.12□3.03 (m, 1H), 2.84-2.74 (m, 1H).

Example 205Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-((dimethylamino)methyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 205F)

Synthesis ofrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-((dimethylamino)methyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 205F)

To a solution of cruderac-(5aR,6S,7R,8R,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-7-(hydroxymethyl)-1-methoxy-6-phenyl-7,8-dihydro-6H-cyclopenta[4,5]furo[1,2-b]pyridin-8a-ol(1, 50 mg, 0.10 mmol) in THF (1 mL) were added formaldehyde (37%solution in water, 30 μL, 33 mg, 0.41 mmol), acetic acid (1.2 μL, 1.3mg, 0.021 mmol) and molecular sieves (ca. 80 mg). The mixture wasstirred for 30 min. Sodium triacetoxyborohydride (85 mg, 0.40 mmol) wasadded, and the mixture was stirred for another 30 min. Then the reactionwas quenched with NaHCO₃(aq), and the mixture was extracted (3×dichloromethane). The combined organic phases were dried (Na₂SO₄),filtered and concentrated. The crude product was taken up inMeCN/DMSO/water+a few drops of TFA. Purification by prep-HPLC (C18,MeCN/H₂O+0.1% TFA) providedrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-((dimethylamino)methyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 205F) as the TFA salt. Yield: 25.1 mg (0.0393 mmol, 39%),white solid; MS (ESI) m/z 525.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.81(b, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.34 (d, J=8.8 Hz, 2H), 7.17-7.08(m, 5H), 6.81-6.75 (m, 2H), 6.20 (s, 1H), 5.91 (b, 1H), 4.03 (s, 3H),3.84-3.76 (m, 1H), 3.57-3.48 (m, 1H), 3.46-3.40 (m, 1H), 3.23 (dd,J=11.0, 7.5 Hz, 1H), 3.18 (d, J=13.7 Hz, 1H), 3.16-3.09 (m, 1H), 3.08(d, J=4.9 Hz, 3H), 2.98 (d, J=4.9 Hz, 3H), 2.75-2.66 (m, 1H).

Example 206Rac-4-((4bR,5R,6R,7S,7aR)-5-((dimethylamino)methyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 206F)

Synthesis of rac-4-((4bR,5R, 6R,7S,7aR)-5-((dimethylamino)methyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 206F)

In a microwave vialrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-((dimethylamino)methyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(1, 19.4 mg, 0.0303 mmol) was dissolved in N,N-dimethylformamide (0.70mL) and water (0.07 mL). Zinc cyanide (18 mg, 0.15 mmol) and zinc (0.8mg, 0.01 mmol) were added, and the mixture was degassed by bubblingargon through it for 5 min. Dppf (4.9 mg, 0.0088 mmol) andTris(dibenzylideneacetone)dipalladium(0) (4.1 mg, 0.0044 mmol) wereadded and the mixture was degassed for another 5 min, then incubated at100° C. for 2 h in total. The mixture was filtered, diluted with MeCN,DMSO and water, and filtered again. The filtrate and the precipitateboth contained the desired product and were separately subjected to HPLCpurification (C18, MeCN/water+0.1% TFA) to provide the desired productrac-4-((4bR,5R,6R,7S,7aR)-5-((dimethylamino)methyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 206F) as its TFA salt. Overall yield: 11.6 mg, 65%, whitesolid; MS (ESI) m/z 472.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (b,1H), 8.22 (s, 1H), 8.17 (s, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.39 (bd, 2H),7.13-7.07 (m, 3H), 6.82-6.76 (m, 2H), 6.27 (s, 1H), 5.98 (s, 1H), 4.04(s, 3H), 3.86-3.78 (m, 1H), 3.61-3.51 (m, 1H), 3.44 (dd, J=11.0, 3.1 Hz,1H), 3.28-3.21 (m, 1H), 3.23 (d, J=13.3 Hz, 1H), 3.18-3.10 (m, 1H), 3.08(d, J=4.8 Hz, 3H), 2.98 (d, J=4.8 Hz, 3H), 2.83-2.73 (m, 1H).

Example 207Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 207aF)Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 207bF)

Synthesis ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3,3-difluoroazetidin-1-yl)methanone(2)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 41 mg, 0.077 mmol) in N,N-dimethylformamide (0.70 mL) at rtunder argon was added HATU (32 mg, 0.084 mmol). After 2 minN,N-diisopropylethylamine (34 uL, 25 mg, 0.20 mmol) was added, and themixture was stirred for 15 min. Another 34 uL (25 mg, 0.20 mmol) DIPEAwere added, followed by 3,3-difluoroazetidine hydrochloride (30 mg, 0.23mmol) and the mixture was stirred at rt for 45 min. Then the mixture wasdiluted with ethyl acetate and washed with brine. The aq. phase wasre-extracted with EtOAc once. Then the combined organic phases weredried (Na₂SO₄), filtered and concentrated. Purification by columnchromatography (SiO₂, 0-5.5% MeOH in dichloromethane) gave 53.5 mg ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3,3-difluoroazetidin-1-yl)methanone(2) as a yellow foam, which was used in the next step without furtherpurification; MS (ESI) m/z 607.2 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-difluoroazetidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3)

To a solution ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3,3-difluoroazetidin-1-yl)methanone(2) (impure material obtained in previous step, 53.5 mg) in THF (0.80mL) at 0° C. was added BH₃-DMS complex in THF (2M, 0.23 mL, 0.46 mmol)and the mixture was stirred at 40° C. for 4 h. Borane adducts of desiredproduct observed. 1 mL MeOH was carefully added at 0° C. and the mixturewas stirred at 60° C. for 1.5 h. The product was isolated usingion-exchange extraction [Phenomenex Strata™-X-C; column was washed withwater, product solution loaded, washed with water (3×), MeCN (3×), MeOH(3×), then product was eluted with 5% NH₄OH(aq) in MeOH (3×)] to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-difluoroazetidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3). Yield: 27.4 mg (0.0461 mmol, 60% over 2 steps); MS (ESI) m/z 593.3[M+1]+.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]-pyridine-3-carbonitrile(Cpd. No. 207aF)Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo-[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 207bF)

In a screw-cap-vial,rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-difluoroazetidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (3, 27.4 mg, 0.0461mmol) was dissolved in N,N-dimethylformamide (0.40 mL) and water (0.04mL), and zinc (0.9 mg, 0.01 mmol) and zinc cyanide (27 mg, 0.23 mmol)were added. The mixture was degassed by bubbling argon through it for 5min. Then dppf (7.7 mg, 0.014 mmol) and Pd₂dba₃ (6.3 mg, 0.0069 mmol)were added. The mixture was degassed by bubbling argon through it foranother 5 min, then the vial was sealed and placed in a preheatedheating block (110° C.). The mixture was stirred for 2 h. Then themixture was filtered, diluted with MeCN, DMSO and water, filtered again,and subjected to purification by HPLC (C18, MeCN/water+0.1% TFA) toprovide the TFA salts of desired products (Cpd. No. 207aF and Cpd. No.207bF) as white solids. Yields and analytical data: (Cpd. No. 207aF):17.6 mg (0.0273 mmol, 59%); MS (ESI) m/z 531.4 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 7.60 (s, 1H), 7.56 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.7 Hz, 2H),7.14-6.99 (m, 5H), 5.97 (bs, 1H), 5.55 (b, 1H), 4.84-4.36 (m, 4H),4.54-4.51 (m, 1H), 3.92 (s, 3H), 3.79 (d, J=13.6 Hz, 1H), 3.37-3.21 (m,2H), 3.07-2.81 (m, 1H). (Cpd. No. 207bF): 5.1 mg (0.0078 mmol, 17%); MS(ESI) m/z 540.2 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.55 (d, J=8.6 Hz,2H), 7.33 (d, J=8.6 Hz, 2H), 7.14□6.98 (m, 5H), 6.94 (s, 1H), 5.79 (bs,1H), 5.43 (b, 1H), 4.99-4.02 (b, 4H), 4.47 (bs, 1H), 3.86 (s, 3H), 3.78(d, J=13.5 Hz, 1H), 3.32-3.13 (b, 2H), 3.04-2.77 (b, 1H).

Example 208Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-(((2,2-difluoroethyl)(methyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 208aF)Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-(((2,2-difluoroethyl)(methyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 208bF)

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-N-(2,2-difluoroethyl)-8,8a-dihydroxy-1-methoxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(2)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 40 mg, 0.075 mmol) in N,N-dimethylformamide (0.70 mL) at rtunder argon was added HATU (31 mg, 0.082 mmol). After 2 minN,N-diisopropylethylamine (33 μL, 24 mg, 0.19 mmol) was added, and themixture was stirred for 15 min. Then another 33 μL (24 mg, 0.19 mmol)DIPEA were added, followed by 2,2-difluoro-N-methyl-ethanaminehydrochloride (29.6 mg, 0.225 mmol), and the mixture was stirred for 2h, then diluted with EtOAc and washed with brine. The aq. phase wasre-extracted with EtOAc once, and the combined organic phases weredried, filtered and concentrated. Purification by column chromatography(SiO₂, 0-5% MeOH in dichloromethane) gave 49 mg of material containingthe productrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-N-(2,2-difluoroethyl)-8,8a-dihydroxy-1-methoxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(2) as an orange foam, which was used in the next step without furtherpurification; MS (ESI) m/z 609.3 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(((2,2-difluoroethyl)(methyl)amino)methyl)-1-methoxy-6-phenyl-5a,6, 7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (3)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-N-(2,2-difluoroethyl)-8,8a-dihydroxy-1-methoxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(2) (impure material obtained in previous step, 49 mg) in THF (0.75 mL)at 0° C. was added BH₃-DMS complex in THF (2M, 0.22 mL, 0.44 mmol) andthe mixture was stirred at 40° C. for 4 h. Then 1 mL MeOH was carefullyadded at 0° C. and the mixture was stirred at 60° C. for 1 h. Theproduct was isolated using ion-exchange extraction [PhenomenexStrata™-X-C; column was washed with water, product solution loaded,washed with water (3×), MeCN (3×), MeOH (3×), then product was elutedwith 5% NH₄OH in MeOH (3×)] to provide the desired product ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(((2,2-difluoroethyl)(methyl)amino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3). Yield: 30.6 mg (0.0514 mmol, 69% over 2 steps), white solid; MS(ESI) m/z 595.3 [M+1]⁺.

Synthesis of rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-(((2,2-difluoroethyl)(methyl)amino)-methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 208aF)rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-(((2,2-difluoroethyl)(methyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 208bF)

In a microwave vial,rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(((2,2-difluoroethyl)(methyl)amino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3, 30.6 mg, 0.0514 mmol) was dissolved in N,N-dimethylformamide (0.40mL) and water (0.04 mL) and zinc (1.2 mg, 0.018 mmol) and zinc cyanide(30.2 mg, 0.257 mmol) were added. The mixture was degassed by bubblingargon through it for 5 min. Dppf (8.6 mg, 0.016 mmol) and Pd₂dba₃ (7.3mg, 0.0080 mmol) were added. The mixture was degassed by bubbling argonthrough it for another 5 min, then the vial was sealed, then placed in apreheated heating block (110° C.). The mixture was stirred for 2 h. Thenthe mixture was filtered, diluted with MeCN, DMSO and water, filteredagain, and subjected to purification by HPLC (C18, MeCN/water+0.1% TFA)to provide the desired productsrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-(((2,2-difluoroethyl)(methyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 208aF and Cpd. No. 208bF) as the corresponding TFA salts.Yields and analytical data: (Cpd. No. 208aF): 17.2 mg (0.0266 mmol,52%), white solid; MS (ESI) m/z 533.3 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 7.60 (s, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H),7.15-6.99 (m, 5H), 6.43 (bt, J=54 Hz, 1H), 5.97 (bs, 1H), 5.59 (b, 1H),5.20-4.00 (b, 2H), 4.66 (b, 1H), 3.92 (s, 3H), 3.79 (d, J=13.9 Hz, 1H).[Remaining protons appear as broad signals between 3.75 and 2.50 ppm,partially overlapping with water peak]. (Cpd. No. 208bF): 4.4 mg (0.0067mmol, 13%), white solid; MS (ESI) m/z 542.2 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 7.54 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 7.14-06.98(m, 5H), 6.94 (s, 1H), 6.70-6.10 (b, 1H), 5.77 (bs, 1H), 5.70-5.00 (b,1H), 4.58 (b, 1H), 3.89 (s, 3H), 3.78 (d, J=13.9 Hz, 1H). [Remainingprotons appear as broad signals between 5.00 and 2.50 ppm, partiallyoverlapping with water peak].

Example 209Rac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-((dimethylamino)methyl)-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(Cpd. No. 209F)

Synthesis ofrac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-((dimethylamino)methyl)-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(Cpd. No. 209F)

To a solution ofrac-(5aR,6S,7R,8R,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(1, 224 mg, 0.421 mmol) in THF (5 mL) were added formaldehyde (37% sln.in water) (0.34 mL, 1.7 mmol), acetic acid (9 μL, 9 mg, 0.2 mmol) andmolecular sieves (ca. 0.5 g). The mixture was stirred for 30 min. Sodiumtriacetoxyborohydride (358 mg, 1.69 mmol) was added, and the mixture wasstirred for another 30 min. Then the reaction was quenched withNaHCO₃(aq), and the mixture was extracted (3× dichloromethane). Thecombined organic phases were dried (Na₂SO₄), filtered and concentrated.Purification by prep HPLC (C18, MeCN/water+0.1% TFA; product fractionswere combined and lyophilized; the so obtained fluffy white solid wastaken up in a few mL of MeCN, frozen and lyophilized again to removewater) providedrac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-((dimethylamino)methyl)-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(Cpd. No. 209F) as the TFA salt. Yield: 143 mg, 50%, white solid; MS(ESI) m/z 559.2 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (b, 1H), 7.36(d, J=8.8 Hz, 2H), 7.15-7.07 (m, 5H), 7.04 (s, 1H), 6.81-6.76 (m, 2H),6.11 (s, 1H), 6.10-5.70 (b, 1H), 3.99 (s, 3H), 3.81-3.71 (m, 1H), 3.51(ddd, J=12.5, 7.5, 4.5 Hz, 1H), 3.43 (dd, J=11.1, 2.9 Hz, 1H), 3.27-3.20(m, 1H), 3.21 (d, J=13.5 Hz, 1H), 3.15-3.07 (m, 1H), 3.07 (d, J=4.7 Hz,3H), 2.98 (d, J=4.7 Hz, 3H), 2.76-2.65 (m, 1H).

Example 210Rac-(5aR,6S,7R,8R,8aR)-5a-(4-cyanophenyl)-8-((dimethylamino)methyl)-8a-hydroxy-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 210F)

Synthesis ofrac-(5aR,6S,7R,8R,8aR)-5a-(4-cyanophenyl)-8-((dimethylamino)methyl)-8a-hydroxy-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 210F)

In a vial,rac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-((dimethylamino)methyl)-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(1) (ca. 86% pure by LCMS, 18.7 mg, 0.0287 mmol) was dissolved inN,N-dimethylformamide (0.40 mL) and water (0.04 mL), and zinc (1 mg,0.02 mmol) and zinc cyanide (20.8 mg, 0.177 mmol) were added. Themixture was degassed by bubbling argon through it for 5 min. Then dppf(5.6 mg, 0.010 mmol) and Pd₂dba₃ (4.7 mg, 0.0051 mmol) were added. Themixture was degassed by bubbling argon through it for another 5 min,then the vial was sealed, then placed in a preheated heating block (110°C.). The mixture was stirred for 2 h. Then the mixture was cooled downto rt, diluted with DMSO and filtered. The filtrate contained some ofthe bis-CN product and a CN/proteo impurity (judged by LCMS—resultingfrom proteodebromination or proteodechlorination). The precipitatelargely consisted of product (judged by LCMS). Precipitate and filtratewere separately subjected to HPLC purification (C18, MeCN/water+0.1%TFA). HPLC purification of the filtrate provided 9.1 mg of a mixture ofthe desired product and the CN/proteo impurity as TFA salts(inseparable) as a white solid. HPLC purification of the precipitateprovided 1.5 mg of a mixture of the desired product and the CN/proteoimpurity as TFA salts (inseparable) as a white solid in addition to 6.2mg (0.010 mmol, 35%) of the pure TFA salt ofrac-(5aR,6S,7R,8R,8aR)-5a-(4-cyanophenyl)-8-((dimethylamino)methyl)-8a-hydroxy-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 210F) as a white hygroscopic solid; MS (ESI) m/z 497.3 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (b, 1H), 7.73 (s, 1H), 7.65 (d, J=8.5Hz, 2H), 7.36 (bd, 2H), 7.15-7.06 (m, 3H), 6.82-6.74 (m, 2H), 6.30 (s,1H), 6.06 (b, 1H), 4.04 (s, 3H), 2.84-3.74 (m, 1H), 3.62-3.52 (m, 1H),3.16 (d, J=13.4 Hz, 1H), 3.19-3.12 (m, 1H), 3.08 (d, J=4.7 Hz, 3H), 2.98(d, J=4.7 Hz, 3H), 2.86-2.76 (m, 1H). [Remaining protons are obscured bywater peak.]

Example 211Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3-fluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 211aF)Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3-fluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 211bF)

Synthesis ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3-fluoroazetidin-1-yl)methanone(2)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 50 mg, 0.094 mmol) in N,N-dimethylformamide (1 mL) at rt underargon was added HATU (40 mg, 0.11 mmol). After 2 minN,N-diisopropylethylamine (42 μL, 31 mg, 0.24 mmol) was added, and themixture was stirred at rt. After 15 min another 42 μL (31 mg, 0.24 mmol)DIPEA were added, followed by 3-fluoroazetidine hydrochloride (31 mg,0.28 mmol) and the mixture was stirred at rt for 10 min. Then themixture was diluted with ethyl acetate and washed with brine. The aq.phase was re-extracted with EtOAc once. Then the combined organic phaseswere dried (Na₂SO₄), filtered and concentrated. Purification by columnchromatography (SiO₂, 0-5% MeOH/dichloromethane) provided 63.6 mg of thestill impure product ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3-fluoroazetidin-1-yl)methanone(2) as a white foam, which was used without further purification. MS(ESI) m/z 589.1 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3-fluoroazetidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3)

To a solution ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3-fluoroazetidin-1-yl)methanone(2, 63.6 mg of the impure product of the previous step) in THF (0.80 mL)at 0° C. was added BH₃-DMS complex in THF (2M, 0.28 mL, 0.56 mmol) andthe mixture was stirred at 4° C. for 4 h. Borane adducts of desiredproduct observed by LCMS. 1 mL MeOH was carefully added at 0° C. and themixture was stirred at 60° C. for 8 h, then at rt for another 1 h. Theproduct was isolated using ion-exchange extraction [PhenomenexStrata™-X-C; column was washed with water, product solution loaded,washed with water (3×), MeCN (3×), MeOH (3×), then product was elutedwith 5% NH₄OH in MeOH (3×)]. The so-obtained product ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3-fluoroazetidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3) was purified by column chromatography (SiO₂, 0-5%MeOH/dichloromethane). Yield: 34.7 mg (0.060 mmol, 64% over 2 steps); MS(ESI) rm/z 575.1 [M+1]+.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3-fluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 211aF)Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3-fluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 211bF)

In a vial,rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3-fluoroazetidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3, 31.8 mg, 0.0552 mmol) was dissolved in N,N-dimethylformamide (0.50mL) and Water (0.05 mL), and zinc (1.2 mg, 0.018 mmol) and zinc cyanide(33 mg, 0.28 mmol) were added. The mixture was degassed by bubblingargon through it for 5 min. Then dppf (9.2 mg, 0.017 mmol) and Pd₂dba₃(7.6 mg, 0.0083 mmol) were added. The mixture was degassed by bubblingargon through it for another 5 min, then the vial was sealed and placedin a preheated heating block (110° C.). The mixture was stirred for 2 h.Then the mixture was diluted with DMSO/MeCN and filtered, and thefiltrate was subjected to purification by HPLC (C18, MeCN/water+0.1%TFA; product fractions combined and lyophilized) to provide the desiredproducts ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3-fluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 211aF) andrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3-fluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 211bF) as their diastereomeric TFA salts (cis/trans ammonium-Hrelative to F, dr ca. 1:1). Yields and analytical data: (Cpd. No. 211aF)(ca. 1:1 mixture of diastereomeric TFA salts): 20.1 mg (0.0321 mmol,58%), white solid; MS (ESI) m/z 513.3 [M+1]⁺. Compounds 211aF and 211bFappear to exist as diastereomeric TFA salts (dr ca. 1:1, i. e.ammonium-proton cis and trans relative to F in each case). In additionto this, the observed signal broadening hampered the detailed analysisof the ¹H-NMRs. Therefore, in the following only selected characteristicNMR signals are listed. ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (b, 0.5H),9.90 (b, 0.5H), 7.61 (s, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.34 (d, J=8.6 Hz,2H), 7.16-6.97 (m, 5H), 6.01 (s, 0.5H), 5.99 (s, 0.5H), 5.70 (b, 0.5H),5.59 (b, 0.5H), 5.52-5.26 (m, 1H), 3.92 (s, 3H). [Remaining protonsappear as broad signals between 4.80 and 2.60 ppm.]. (Cpd. No. 211bF)(ca. 1:1 mixture of diastereomeric TFA salts): 2.3 mg (0.0036 mmol, 7%),white solid; MS (ESI) m/z 522.4 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ10.44 (b, 0.5H), 9.72 (b, 0.5H), 7.57 (d, J=8.4 Hz, 2H), 7.36-7.31 (m,2H), 7.17-6.93 (m, 6H), 5.84 (bs, 0.5H), 5.82 (s, 0.5H), 5.53 (bd, J=6.3Hz, 0.5H), 5.43 (d, J=6.3 Hz, 0.5H), 5.52-5.25 (m, 1H), 3.87 (s, 3H).[Remaining protons appear as broad signals between 4.75 and 2.80 ppm.]

Example 212(5aR,6S,7S,8R,8aS)-7-(azetidin-1-ylmethyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 212F)

Synthesis ofrac-azetidin-1-yl((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)methanone(2)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 50 mg, 0.094 mmol) in N,N-dimethylformamide (1 mL) at rt underargon was added HATU (40 mg, 0.11 mmol). After 2 minN,N-diisopropylethylamine (42 μL, 31 mg, 0.24 mmol) was added, and themixture was stirred for 15 min. Then another 42 μL (31 mg, 0.24 mmol)DIPEA were added, followed by azetidine hydrochloride (26 mg, 0.28 mmol)and the mixture was stirred at rt for 45 min. Then the mixture wasdiluted with ethyl acetate and washed with brine. The aq. phase wasre-extracted with EtOAc once. Then the combined organic phases weredried (Na₂SO₄), filtered and concentrated. Purification by columnchromatography (SiO₂, 0-5% MeOH/dichloromethane) yielded 58.7 mg of thestill impure product ofrac-azetidin-1-yl((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)methanone(2) as a white foam; MS (ESI) m/z 571.2 [M+1]⁺. This material was usedwithout further purification.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-7-(azetidin-1-ylmethyl)-5a-(4-bromophenyl)-3-chloro-1-methoxy-6-phenyl-5a,6,7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (3)

To a solution ofrac-azetidin-1-yl((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)methanone(2, 58.7 mg of impure product of the previous step) in THF (0.80 mL) at0° C. was added BH₃-DMS complex in THF (2M, 0.28 mL, 0.56 mmol) and themixture was stirred at 40° C. for 4 h. Borane adducts of desired productobserved by LCMS. 1 mL MeOH was carefully added at 0° C. and the mixturewas stirred at 60° C. for 8 h, then at rt for another 2 h. Then productwas isolated using ion-exchange extraction [Phenomenex Strata™-X-C;column was washed with water, product solution loaded, washed with water(3×), MeCN (3×), MeOH (3×), then product was eluted with 5% NH₄OH inMeOH (3×)]. The so-obtained material was repurified by columnchromatography (SiO₂, 0-10% MeOH/dichloromethane) to provide the desiredproduct ofrac-(5aR,6S,7S,8R,8aS)-7-(azetidin-1-ylmethyl)-5a-(4-bromophenyl)-3-chloro-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3) as a white solid. Yield: 14.1 mg (0.0253 mmol, 27%, 2 steps); MS(ESI) m/z 557.3 [M+1]⁺.

Synthesis of(5aR,6S,7S,8R,8aS)-7-(azetidin-1-ylmethyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 212F)

In a vial,rac-(5aR,6S,7S,8R,8aS)-7-(azetidin-1-ylmethyl)-5a-(4-bromophenyl)-3-chloro-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3, 14.1 mg, 0.0253 mmol) was dissolved in N,N-dimethylformamide (0.40mL) and water (0.04 mL) and zinc (0.8 mg, 0.01 mmol) and zinc cyanide(15 mg, 0.13 mmol) were added. The mixture was degassed by bubblingargon through it for 5 min. Then dppf (4.2 mg, 0.0076 mmol) and Pd₂dba₃(3.5 mg, 0.0038 mmol) were added. The mixture was degassed by bubblingargon through it for another 5 min, then the vial was sealed and placedin a preheated heating block (110° C.). The mixture was stirred for 2 hThen the mixture was diluted with DMSO/MeCN and filtered, and thefiltrate was subjected to purification by HPLC (C18, MeCN/water+0.1%TFA; product fractions were combined and lyophilized) to provide 4.8 mgof slightly impure product ofrac-(5aR,6S,7S,8R,8aS)-7-(azetidin-1-ylmethyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 14) as the TFA salt containing small amounts (ca. 10%) of themonocyanated product, and 4.7 mg (31%) of the pure TFA salt ofrac-(5aR,6S,7S,8R,8aS)-7-(azetidin-1-ylmethyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrileas a white solid; The enantiomers were separated by chiral HPLC[CHIRALPAK IG (4.6×250) mm, 5μ] in CO₂/IPA/TEA (60:40:0.2).

Peak 1 (Cpd. No. 212F, 505 mg), Rt=2.03 min, ee: 98.76%, [α]D −101° (c0.40, CHCl3); MS (ESI) m/z 495.16[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆)7.54-7.50 (m, 3H), 7.32 (d, J=7.6 Hz, 2H), 7.08-7.07 (m, 2H), 7.02-6.96(m, 3H), 5.82 (s, 1H), 4.46 (s, 1H), 3.89 (s, 3H), 3.80 (d, J=14.0 Hz,1H), 3.10 (bs, 4H), 2.95 (bs, 1H), 2.62-2.59 (m, 1H), 2.32 (d, J=5.2 Hz,1H), 1.92-1.90 (m, 2H), 1.03 (bs, 1H). Peak-2 (455 mg), R_(t)=3.77 min,ee: 99.50%, [α]_(D) +120.2° (c 0.25, CHCl₃); MS (ESI) m/z 495.16[M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) 7.54-7.50 (m, 3H), 7.32 (d, J=7.6 Hz, 2H),7.10-7.07 (m, 2H), 7.02-6.97 (m, 3H), 5.82 (s, 1H), 4.46 (s, 1H), 3.89(s, 3H), 3.80 (d, J=14.0 Hz, 1H), 3.10 (bs, 4H), 2.95 (bs, 1H),2.62-2.59 (m, 1H), 2.32 (d, J=5.2 Hz, 1H), 1.92-1.90 (m, 2H), 1.04-1.02(m, 1H).

Example 213Rac-(5aR,6S,7R,8R,8aR)-5a-(4-cyanophenyl)-8-((4,4-difluoropiperidin-1-yl)methyl)-8a-hydroxy-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 213F)

Synthesis of 3,3-difluoropentane-1,5-diyl dimethanesulfonate (2)

[1] Ester reduction: To a solution of diethyl 3,3-difluoropentanedioate(1, 142 mg, 0.632 mmol) in THF (7 mL) at 0° C. was added LAH (57 mg, 1.5mmol) and the mixture was stirred at rt. After 2.5 h 0.3 mL water wereadded at 0° C., followed by 0.3 mL 12.5% NaOH (aq) and ca. 500 mg ofNa₂SO₄. The mixture was stirred for 10 min at rt, then filtered (rinsedwith THF) and concentrated to give 103 mg of3,3-difluoropentane-1,5-diol as a cloudy oil, which was used withoutfurther purification. 1H NMR (400 MHz, DMSO-d₆) δ 4.64 (t, J=5.1 Hz,2H), 3.56 (dt, J=6.9, 5.1 Hz, 4H), 2.06 (tt, J=17.0, 6.9 Hz, 4H).

[2] Mesylation: To a solution of 3,3-difluoropentane-1,5-diol (103 mg ofthe crude product obtained in the previous step) in dichloromethane (4.2mL) at −78° C. were added triethylamine (0.35 mL, 0.25 g, 2.5 mmol) andmethanesulfonyl chloride (0.12 mL, 0.18 g, 1.6 mmol) and the mixture wasstirred at −78° C. for 30 min, then warmed up to 0° C. and stirred foranother 1.5 h. Then the reaction was quenched (water) and the mixturewas extracted (3× dichloromethane). The combined organic phases weredried (Na₂SO₄), filtered and concentrated. The residue was taken up inEtOAc and washed with water and brine. The organic phase was dried(Na₂SO₄), filtered and concentrated to give 192 mg of3,3-difluoropentane-1,5-diyl dimethanesulfonate (2) as a yellowish oil,which was used without further purification. 1H NMR (400 MHz, CDCl₃) δ4.44 (t, J=6.4 Hz, 4H), 3.05 (s, 6H), 2.41 (tt, J=16.1, 6.4 Hz, 4H).

Synthesis ofrac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-((4,4-difluoropiperidin-1-yl)methyl)-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,6, 7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol (4)

A solution ofrac-(5aR,6S,7R,8R,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(3, 30 mg, 0.056 mmol), N,N-diisopropylethylamine (36 μL, 27 mg, 0.21mmol) and (3,3-difluoro-5-methylsulfonyloxy-pentyl) methanesulfonate (2,22 mg, 0.074 mmol) in N,N-dimethylformamide (0.60 mL) was stirred at 80°C. After 5 h another 36 μL (27 mg, 0.21 mmol) DIPEA and 20 mg (0.067mmol) bis-mesylate (2) in 0.30 mL N,N-dimethylformamide were added, andstirring at 80° C. was continued. After 7 h total, the mixture wascooled down to rt. The product was isolated by ion-exchange extractionas a mixture with the SM and other amines [Phenomenex Strata™-X-C;column was washed with water, product solution loaded, washed with water(3×), MeCN (3×), MeOH (3×), then product was eluted with 5% NH₄OH inMeOH (3×)]. The so-obtained product mixture (23 mg) ofrac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-((4,4-difluoropiperidin-1-yl)methyl)-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(4), was used in the next step without further purification.

Synthesis ofrac-(5aR,6S,7R,8R,8aR)-5a-(4-cyanophenyl)-8-((4,4-difluoropiperidin-1-yl)methyl)-8a-hydroxy-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 213F)

In a vial, cruderac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-((4,4-difluoropiperidin-1-yl)methyl)-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol(4, 23 mg obtained in the previous step) was dissolved inN,N-dimethylformamide (0.40 mL) and water (0.04 mL), and zinc (0.9 mg,0.01 mmol) and zinc cyanide (22 mg, 0.19 mmol) were added. The mixturewas degassed by bubbling argon through it for 5 min. Then dppf (6.1 mg,0.011 mmol) and Pd₂dba₃ (5.1 mg, 0.0056 mmol) were added. The mixturewas degassed by bubbling argon through it for another 5 min, then thevial was sealed, then placed in a preheated heating block (110° C.). Themixture was stirred for 2 h. Then the mixture was filtered, diluted withMeCN, DMSO and water, filtered again, and subjected to repeatedpurification by HPLC (C18, MeCN/water+0.1% TFA). The so-obtained product(free base) was finally purified by preparative TLC (SiO₂,dichloromethane/2% MeOH) to provide the pure desired productrac-(5aR,6S,7R,8R,8aR)-5a-(4-cyanophenyl)-8-((4,4-difluoropiperidin-1-yl)methyl)-8a-hydroxy-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 213F). Yield: 2.0 mg (6%, 2 steps), white solid; MS (ESI) m/z573.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (s, 1H), 7.61 (d, J=8.5Hz, 2H), 7.36 (bd, 2H), 7.12-7.03 (m, 3H), 6.82-6.75 (m, 2H), 6.10-5.90(b, 1H), 5.88 (b, 1H), 4.00 (s, 3H), 3.47-3.38 (m, 1H), 3.24 (d, J=13.6Hz, 1H), 3.20-3.12 (m, 1H), 3.15-2.63 (b, 8H), 2.14-1.92 (b, 4H).

Example 214Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-dimethylmorpholino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 214F)

Synthesis ofrac-(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-7-methylene-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(2)

A stirred solution ofrac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(1, 95 mg, 0.008 mmol) in THF (3 mL) was cooled to −78° C. and lithiumdiisopropyl amide (1.95 M in THF, 0.43 mL, 0.85 mmol) was added slowly.After 15 minutes dimethyl(methylene) ammonium iodide (192 mg, 1.04 mmol)was added in 1 portion. The reaction mixture was allowed to graduallywarm to room temperature. After stirring at room temperature for 3 hoursthe reaction mixture was diluted with 10 mL of ethyl acetate and 10 mLof saturated aqueous sodium bicarbonate. The layers were separated andthe aqueous phase extracted with ethyl acetate three times. The combinedorganic material was washed with brine and dried over magnesium sulfate.Purification by silica gel chromatography eluting with hexanes and ethylacetate affordedrac-(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-7-methylene-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(2) as a tan solid. Yield: 55 mg, 56%; LCMS (ESI) m/z 469.5 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-dimethylmorpholino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 214F)

Rac-(5aR,6R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-7-methylene-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one(2, 26.0 mg, 0.07 mmol) was dissolved in THF (0.3 mL) and the mixturewas stirred for 3 h. The solvent was then removed under a stream ofnitrogen. The oily residue was taken up in acetonitrile (0.3 mL) andstirred at rt while sodium triacetoxyborohydride (44 mg, 0.21 mmol) wasadded. After 2 hr the mixture was diluted with ethyl acetate andsaturated aqueous ammonium chloride was added. The aqueous material wasextracted with ethyl acetate 3 times, and the combined organic materialwas washed with brine and dried over magnesium sulfate. The solvent wasremoved in vacuo and residue purified by RP-HPLC. The fractionscontaining product were then passed through an ion exchange column,washing the material first with water, then methanol, then acetonitrile.The product was then eluted with a solution of methanol:dichloromethane: aqueous NH₄OH (75:20:5), and the solvent rotavapped.The residue was taken up in a water/acetonitrile mixture, frozen andlyophilized to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-dimethylmorpholino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(Cpd. No. 214F) as a white solid. Yield: 4.9 mg, 17%; LCMS (ESI) m/z586.5 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 1H), 7.55 (s, 1H),7.17 (d, J=8 Hz, 2H), 7.09-7.00 (m, 7H), 5.92 (s, 1H), 4.39 (d, J=6H),3.88 (d, J=12 Hz, 1H), 3.67-3.65 (m, 1H), 3.57-3.55 (m, 1H), 3.16-3.09(m, 4H), 2.73-2.62 (m, 2H), 2.02-1.99 (m, 1H), 0.83 (s, 3H), 0.76 (s,3H).

Example 215Rac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3-(difluoromethyl)azetidin-1-yl)methanone(Cpd. No. 215F)

Synthesis ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3-(difluoromethyl)azetidin-1-yl)methanone(Cpd. No. 215F)

To a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 0.08 g, 0.14 mmol) in N,N-dimethylformamide (1.76 mL) was addedHATU (55.8 mg, 0.14 mmol) and then N,N diisopropylamine (0.12 mL, 0.70mmol) dropwise 2 minutes later. 3-(difluoromethyl)azetidinehydrochloride (60.2 mg, 0.42 mmol) was added in 1 portion. After 65minutes the mixture was diluted with water and EtOAc and washed organicphase with water 2× and brine 1×. The organic material was dried overmagnesium sulfate, filtered, and rotavapped. The crude material waspurified by by silica gel column chromatography eluting with hexanes andethyl acetate to affordrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3-(difluoromethyl)azetidin-1-yl)methanone(Cpd. No. 215F) as a white solid. Yield: 82 mg, 94%; LCMS (ESI) m/z621.3, 623.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.15 (d, J=8.3 Hz, 2H),7.04-6.93 (m, 5H), 6.93-6.84 (m, 3H), 6.30 (t, J=56 Hz, 1H) 5.57 (d,J=13.1 Hz, 1H), 5.18 (s, 1H), 4.68-4.58 (m, 2H), 4.53-4.22 (m, 3H), 3.87(d, J=8.7 Hz, 1H), 3.84-3.66 (m, 6H).

Example 216Rac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3-(difluoromethyl)azetidin-1-yl)methanone(Cpd. No. 216F)

Synthesis ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3-(difluoromethyl)azetidin-1-yl)methanone(Cpd. No. 216F)

To a stirred solution ofrac-[(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-7,8-dihydro-6H-cyclopenta[4,5]furo[1,2-d]pyridin-7-yl]-[3-(difluoromethyl)azetidin-1-yl]methanone(0.08 g, 0.13200 mmol) in THF (2 mL) was added boranemethylsulfanylmethane (2.0 M in THF, 0.66 mL, 1.32 mmol). After 10 minthe reaction was warmed to 40° C. After 14 the reaction was cooled toroom temperature and methanol (1.7 mL) was slowly added. Subsequentlythe reaction was heated to 70° C. After 3.5 hours the pot was cooled tort. The solvent was rotavapped and the residue was purified via ionexchange chromatography, eluting with methanol twice, acetonitriletwice, and then eluting the product with a MeOH:NH₄OH:dichloromethane(75:5:20) solvent system. The solvent was removed in vacuum to affordRac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3-(difluoromethyl)azetidin-1-yl)methanone(Cpd. No. 216F) as a white foam. Yield: 57 mg, 71%; LCMS (ESI) m/z 607.1609.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.24-7.15 (m, 2H), 7.10-7.02(m, 5H), 7.02-6.89 (m, 3H), 6.82 (s, 1H), 6.16 (td, J=60 Hz, 5.3 Hz,1H), 5.52 (s, 1H), 5.32 (s, 1H), 4.35 (d, J=4.1 Hz, 1H), 3.80 (s, 3H),3.66 (d, J=14.2 Hz, 1H), 3.28-3.18 (m, 10H), 3.05 (t, J=6.7 Hz, 2H),2.92-2.73 (m, 2H), 2.63-2.54 (m, 2H), 2.30-2.21 (m, 1H).

Example 217Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 217F)

Synthesis ofrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 217F)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 0.03 g, 0.046 mmol), dicyanozinc (32.45 mg, 0.276 mmol), dppf (20.4mg, 0.037 mmol), and zinc (2.9 mg, 0.046 mmol) were dissolved inN,N-dimethylformamide (0.460 mL) and water (0.040 mL). The mixture wassparged with an argon balloon for 5 min thentris(dibenzylideneacetone)dipalladium(0) (16.8 mg, 0.018 mmol) was addedand the reaction was stirred in heating block at 120° C. After 90minutes the pot was cooled to room temperature. The mixture was dilutedwith methanol, filtered through celite and the volatile solvent removedin vacuo. The residue was taken up in DMSO and purified by RP-HPLC toaffordrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 217F). Yield: 3.8 mg, 13%; LCMS (ESI) m/z 554.4, 556.3 [M+1]⁺;¹H NMR (400 MHz, Methanol-d₄) δ 7.13-6.99 (m, 6H), 6.99-6.92 (m, 3H),6.75 (s, 2H), 6.03 (td, J=56 Hz, 4.2 Hz, 1H), 4.61-4.53 (m, 3H), 3.94(s, 3H), 3.87-3.77 (m, 2H), 3.75 (bs, 1H), 3.57 (bs, 1H), 3.03 (bs, 1H),2.74 (bs, 1H).

Example 218Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 218F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 218F)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 0.03 g, 0.04600 mmol), dicyanozinc (32.4 mg, 0.276 mmol), dppf (20.4mg, 0.037 mmol), and zinc (2.9 mg, 0.046 mmol) were dissolved inN,N-dimethylformamide (0.460 mL) and water (0.040 mL). The mixture wassparged with an argon balloon for 5 min thenTris(dibenzylideneacetone)dipalladium(0) (16.8 mg, 0.0180 mmol) wasadded and the reaction was stirred in heating block at 120° C. After 90minutes the pot was cooled to room temperature. The mixture was dilutedwith methanol, filtered through celite and the volatile solvent removedin vacuo. The residue was taken up in DMSO and purified by RP-HPLC toaffordrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 218F). Yield: 5.3 mg, 21%; LCMS (ESI) m/z 545.5 [M+1]⁺; ¹H NMR(400 MHz, Methanol-d₄) δ 7.46-7.35 (m, 4H), 7.24 (d, J=0.5 Hz, 1H),7.11-6.93 (m, 5H), 5.98 (td, J=60.0, 4.0 Hz, 1H), 4.81-4.67 (m, 2H),4.63-4.53 (m, 2H), 3.98 (s, 3H), 3.82 (d, J=14.4 Hz, 1H), 3.47-3.28 (m,3H), 3.30-3.15 (m, 2H), 3.05 (t, J=11.8 Hz, 1H), 2.88-2.73 (m, 1H), 2.52(dd, J=12.5, 3.0 Hz, 1H), 1.27 (s, 1H).

Example 219Rac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methanone(Cpd. No. 219F)

Synthesis ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methanone(Cpd. No. 219F)

To a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 0.09 g, 0.169 mmol) in N,N-dimethylformamide (1.76 mL) wasadded HATU (67.4 mg, 0.177 mmol) and then N, N diisopropylamine (0.15mL, 0.84 mmol) was dropwise 2 minutes later. After 20 minutes2,2-difluoro-5-azaspiro[2.3]hexane hydrochloride (78.8 mg, 0.510 mmol)was added in 1 portion. After 30 min the mixture was diluted with waterand EtOAc and the organic material was washed with water twice and withbrine once. The organic material was dried over magnesium sulfate,filtered, and rotavapped. The crude material was purified by silica gelchromatography eluting with hexanes and EtOAc to afford the productrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methanone(Cpd. No. 219F). Yield: 83 mg, 78%. LCMS (ESI) m/z 633.3, 635.3[M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 7.21-7.14 (m, 2H), 7.07-6.88 (m, 8H), 5.60(s, 1H), 5.55 (s, 1H), 5.37-5.29 (m, 1H), 4.77 (d, J=8.5 Hz, 1H),4.70-4.58 (m, 2H), 4.46 (d, J=9.5 Hz, 1H), 4.32 (d, J=13.7 Hz, 1H),3.98-3.83 (m, 3H), 3.81 (d, J=1.8 Hz, 3H), 1.80-1.74 (m, 2H).

Example 220Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 220F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methyl)-1-methoxy-6-phenyl-5a,6,7, 8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd.No. 220F)

To a stirred solution ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methanone(1, 0.08 g, 0.126 mmol) in THF (1.76 mL) borane dimethylsulfide solution(2.0 M in THF, 0.50 mL, 1 mmol) was added. After 2 minutes the pot waswarmed to 40° C. The reaction was stirred 12 hr and then cooled to rtand added methanol (1.7 mL) was added over 5 min to quench reaction. Themixture was then warmed to 60° C. for 8 hours and the reaction wascooled to room temperature and the solvent removed in vacuo. The residuewas taken up in acetonitrile and purified by ion exchangechromatography, washing the column sequentially with water,acetonitrile, and methanol, and subsequently eluting product with asolution of 75:25:5 methanol:dichloromethane:ammonium hydroxide. Thesolvent was removed in vacuo and the residue was taken up in a mixtureof acetonitrile and water, frozen, and lyophilized to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 220F) as a fluffy white solid. Yield: 61 mg, 78%; LCMS (ESI)m/z 619.3, 621.1 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.19 (d, J=8.7 Hz,2H), 7.11-6.98 (m, 3H), 7.01-6.91 (m, 3H), 6.82 (s, 1H), 5.53 (bs, 1H),5.20 (bs, 1H), 4.37 (bs, 1H), 3.81 (s, 3H), 3.67 (d, J=14.2 Hz, 1H),3.44-3.41 (m, 1H). 3.28-3.17 (m, 2H), 2.91 (bs, 1H), 2.69 (bs, 1H), 2.34(bs, 1H), 1.50 (m, 2H).

Example 221Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 221F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 221F)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 0.040 g, 0.061 mmol), dicyanozinc (50.3 mg, 0.43 mmol), dppf (27.1mg, 0.049 mmol), and zinc (3.9 mg, 0.061 mmol) were dissolved inN,N-dimethylformamide (0.61 mL) and water (0.06 mL). The solution wassparged with an argon balloon for 10 minutes thenTris(dibenzylideneacetone)dipalladium(0) (22.4 mg, 0.024 mmol) wasadded. The vial was sealed and stirred at 120° C. for 1 hr and thereaction was cooled to rt. The mixture was diluted with methanol and afew drops of DMSO and filtered through celite, washing the pad severaltimes with methanol. The volatile solvent was removed in vacuo and theresidue taken up in DMSO, filtered through a syringe filter thenpurified on RP-HPLC to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 221F). Yield: 3.5 mg, 11%; LCMS (ESI) m/z 557.3 [M+1]⁺; 1H NMR(400 MHz, DMSO-d₆) δ 7.51 (s, 1H), 7.48 (d, J=8.7 Hz, 2H), 7.31 (d,J=8.7 Hz, 3H), 7.10-6.93 (m, 7H), 5.82 (s, 1H), 5.48 (s, 1H), 4.47-4.41(m, 2H), 3.86 (s, 4H), 3.74 (d, J=14.2 Hz, 1H), 3.39 (dd, J=20.5, 7.4Hz, 3H), 3.25 (dd, J=14.5, 7.5 Hz, 3H), 3.04-2.88 (m, 1H), 2.77-2.64 (m,3H), 2.44-2.31 (m, 2H), 2.25-2.17 (m, 2H), 1.71-1.53 (m, 3H), 1.50 (dd,J=9.9, 7.2 Hz, 3H).

Example 222Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 222F)

Synthesis ofrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 222F)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 0.04 g, 0.061 mmol), dicyanozinc (50.3 mg, 0.43 mmol), dppf (27.1mg, 0.049 mmol), and zinc (3.9 g, 0.061 mmol) were dissolved inN,N-dimethylformamide (0.61 mL) and water (0.06 mL). The solution wassparged with an argon balloon for 10 min thenTris(dibenzylideneacetone)dipalladium(0) (22.4 mg, 0.024 mmol) wasadded. The vial was sealed and stirred at 120° C. for 1 hr and thereaction was cooled to rt. The mixture was diluted with methanol and afew drops of DMSO and filtered through celite, washing the pad severaltimes with methanol. The volatile solvent was removed in vacuo and theresidue taken up in DMSO, filtered through a syringe filter thenpurified on RP-HPLC to affordrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((1,1-difluoro-4-azaspiro[2.3]hexan-4-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 222F). Yield: 3.3 mg, 9%; LCMS (ESI) m/z 566.3, 568.4 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 7.50-7.43 (m, 2H), 7.34-7.27 (m, 2H), 7.05(t, J=7.3 Hz, 3H), 6.97 (dd, J=9.7, 7.4 Hz, 3H), 6.85 (s, 1H), 5.64 (s,1H), 5.35 (s, 1H), 4.39 (d, J=4.0 Hz, 1H), 3.81 (s, 4H), 3.73 (d, J=14.1Hz, 1H), 3.38 (dd, J=19.6, 7.5 Hz, 3H), 3.01-2.90 (m, 2H), 2.78-2.65 (m,3H), 2.44-2.32 (m, 2H), 2.21 (t, J=6.3 Hz, 2H), 1.59 (s, OH), 1.50 (dd,J=9.7, 7.4 Hz, 2H).

Example 223Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-7-((methylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 223F)

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(2)

To a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 0.1 g, 0.175 mmol) in N,N-dimethylformamide (1.0 mL) was addedHATU (69.7 mg, 0.183 mmol) and then N,N diisopropylamine (0.15 mL, 0.87mmol). After 30 minutes methyl amine (2.0 M solution, 0.90 mL, 1.8 mmol)was added slowly. After 2 hr the reaction mixture was diluted with ethylacetate and washed sequentially with saturated aqueous NH₄Cl, water, andbrine, and then dried over magnesium sulfate. Purification was carriedout via silica gel chromatography eluting with dichloromethane and ethylacetate to afford pure productrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(2). Yield: 97 mg, 99%; LCMS (ESI) m/z 547.3 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-7-((methylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 223F)

To a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(2, 0.09 g, 0.166 mmol) in THF (4.0 mL) was added boranemethylsulfanylmethane (2.0 M in THF, 0.85 mL, 1.71 mmol) dropwise andthe reaction was warmed to 35° C. After 4.5 hr the reaction was cooledto rt and methanol (1 mL) was added slowly while stirring vigorouslyuntil bubbling ceased, and then the mixture was heated to 65° C. for 19hours. The vial was cooled to room temperature and solvent removed invacuo. The residue was taken up in a mixture of dichloromethane andmethanol, then purified on strata ion exchange column, washing firstwith acetonitrile and methanol, then eluting the product with severalwashes with a solution of 75:25:5 methanol: dichloromethane: ammoniumhydroxide. The solvent was removed in vacuo, the residue was taken up ina mixture of acetonitrile and water, and the mixture was then frozen andlyophilized to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-7-((methylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 223F) as a fluffy white powder. Yield: 68 mg, 76%; LCMS (ESI)m/z 531.3, 533.1 [M+1]⁺; ¹H NMR (400 MHz, Methanol-d₄) δ 7.22-7.14 (m,2H), 7.17-6.94 (m, 8H), 6.74 (s, 1H), 4.70 (dd, J=5.0, 0.5 Hz, 1H), 4.40(d, J=14.2 Hz, 1H), 3.92 (s, 3H), 3.97-3.86 (m, 1H), 2.97 (d, J=0.5 Hz,1H), 2.87-2.76 (m, 1H), 2.79 (s, 4H), 2.01 (s, 1H).

Example 224Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-((methylamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 224F)

Synthesis ofrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-((methylamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 224F)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-7-((methylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 0.03 g, 0.056 mmol), dicyanozinc (46.0 mg, 0.39 mmol), dppf (31.0mg, 0.056 mmol), and zinc (3.6 mg, 0.056 mmol) were dissolved in water(0.056 mL) and N,N-dimethylformamide (0.56 mL) that had been previouslysparged with argon for 1 hr. Tris(dibenzylideneacetone)dipalladium(0)(22.4 mg, 0.024 mmol) was added, the vial was sealed and stirred at 120°C. After 45 minutes the reaction was cooled to room temperature, dilutedwith methanol and filtered through celite, washing the pad several timeswith more methanol. The filtrate was rotavapped, taken up in DMSO andpurified via RP-HPLC to affordrac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-((methylamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 224F). Yield: 3.2 g, 12%; LCMS (ESI) m/z 522.4, 524.2 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 7.49 (d, J=8.7 Hz, 2H), 7.34-7.27 (m, 2H),7.04 (dd, J=7.9, 6.5 Hz, 2H), 7.01-6.91 (m, 4H), 6.87 (s, 1H), 5.60 (s,1H), 4.46 (d, J=4.4 Hz, 1H), 3.81 (s, 3H), 3.76 (d, J=15 Hz, 1H),3.16-3.08 (m, 1H), 2.77-2.69 (m, 1H), 2.69-2.56 (m, 1H), 2.48-2.30 (m,1H), 2.23 (s, 4H), 2.19 (d, J=6.2 Hz, 1H), 1.63-1.52 (m, 1H).

Example 225Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-((methylamino)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 225F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-((methylamino)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 225F)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-7-((methylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 0.03 g, 0.056 mmol), dicyanozinc (46.0 mg, 0.39 mmol), dppf (31.0mg, 0.056 mmol), and zinc (3.6 mg, 0.056 mmol) were dissolved in water(0.056 mL) and N,N-dimethylformamide (0.560 mL) that had previously beensparged with argon for 1 hour. Tris(dibenzylideneacetone)dipalladium(0)(22.4 mg, 0.024 mmol) was added, the vial was sealed and stirred at 120°C. for 45 minutes. The reaction was cooled to room temperature, dilutedwith methanol and filtered through celite, washing the pad several timeswith more methanol. The filtrate was rotavapped, taken up in DMSO andpurified via RP-HPLC to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-((methylamino)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 225F). Yield 15.3 mg (58%). LCMS (ESI) m/z 469.2 [M+1]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 7.52 (s, 1H), 7.51-7.47 (m, 2H), 7.35-7.27 (m,2H), 7.09-6.92 (m, 6H), 5.77 (s, 1H), 4.51 (d, J=4.3 Hz, 1H), 3.86 (s,3H), 3.77 (d, J=14.3 Hz, 1H), 3.10 (ddt, J=13.3, 8.2, 3.7 Hz, 1H), 2.60(dd, J=12.0, 8.6 Hz, 1H), 2.42 (dd, J=11.8, 3.1 Hz, 1H), 2.20 (s, 3H),2.18 (d, J=7.3 Hz, 1H).

Example 226Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-((tert-butylamino)methyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 226F)

Synthesis of rac-methyl(4bR,5S,6R,7S,7aR)-7a-(4-bromophenyl)-5-(tert-butylcarbamoyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(2)

Rac-methyl(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-cyano-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(1, 100 mg, 0.192 mmol) was dissolved in acetic acid (2.0 mL) and2-methylpropan-2-ol (1.99 mL, 20.9 mmol). The solution was stirredvigorously at room temperature while H₂SO₄ (0.06 mL) was added dropwise.The reaction was then warmed to 40° C. for 17 hours and more H₂SO₄ (0.01mL) was added. After 30 hours the reaction was cooled to roomtemperature and saturated aqueous NaHCO₃ (5 mL) was added slowly andthis material was extracted with ethyl acetate three times, the organicmaterial was then dried over magnesium sulfate, filtered and solventremoved in vacuo. The crude residue was purified by RP-HPLC to affordrac-methyl(4bR,5S,6R,7S,7aR)-7a-(4-bromophenyl)-5-(tert-butylcarbamoyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(2). Yield: 70.6 mg, 62%; LCMS (ESI) m/z 591.3, 593.2 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 8.22 (s, 1H), 8.19 (s, 1H), 7.35-7.28 (m, 3H),7.25-7.17 (m, 2H), 7.09-7.03 (m, 4H), 6.94 (s, 1H), 6.78 (dd, J=6.7, 3.0Hz, 3H), 5.99 (s, 1H), 4.08 (dd, J=13.9, 10.5 Hz, 1H), 4.04 (s, 1H),3.55 (d, J=10.5 Hz, 1H), 3.47 (d, J=13.9 Hz, 1H), 3.39 (s, 3H), 1.35 (s,9H).

Synthesis ofrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-((tert-butylamino)methyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 226F)

Rac-methyl(4bR,5S,6R,7S,7aR)-7a-(4-bromophenyl)-5-(tert-butylcarbamoyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(2, 65.0 mg, 0.109 mmol) was dissolved in THF (2.7 mL). Borane;methylsulfanylmethane (1.5 6 mL, 3.12 mmol) was added dropwise and thereaction warmed to 35° C. After stirring 12 hours, the reaction wascooled to room temperature and methanol (1.3 mL) was added over 5minutes to quench the reaction, and the mixture then warmed to 60° C.After stirring for 6 hours the pot was cooled to room temperature andsolvent removed in vacuo. The residue was then purified via RP-HPLC toaffordrac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-((tert-butylamino)methyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 226F). Yield: 18.0 mg, 30%; LCMS (ESI) m/z 553.4, 555.5[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (d, J=2.4 Hz, 1H), 8.11 (s,1H), 7.31 (d, J=8.2 Hz, 3H), 7.14-7.04 (m, 7H), 6.78 (d, J=6.6 Hz, 3H),6.49 (d, J=0.5 Hz, 1H), 3.98 (s, 3H), 3.98 (d, J=1.9 Hz, 1H), 3.66 (m,2H), 3.47 (d, J=11.1 Hz, 1H), 3.28 (d, J=13.6 Hz, 2H), 3.17 (dd, J=11.2,6.0 Hz, 1H), 2.87 (m, 2H), 2.68-2.62 (m, 1H), 1.37 (s, 9H).

Example 227Rac-(5aR,6S,7R,8S,8aR)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(Cpd. No. 227F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylmethanesulfonate (2)

To a solution ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol(1, 46 mg, 0.089 mmol) in dichloromethane (1 mL) was addedtrimethylamine (37 □L, 0.27 mmol) and methanesulfonyl chloride (10 μL,0.13 mmol) dropwise. The reaction was stirred at room temperature for 2h. The resulting mixture was diluted with methanol and purified viaRP-HPLC (C18, 0.1% trifluoroacetic acid in acetonitrile/water=15-50%) toaffordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylmethanesulfonate (2, trifluoroacetic acid salt) as a white solid. Yield:34 mg, 64%; MS (ESI) m/z 595.4[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8S,8aR)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(Cpd. No. 227F)

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylmethanesulfonate (2, trifluoroacetic acid salt, 32 mg, 0.054 mmol) andpotassium cyanide (7 mg, 0.11 mmol) were dissolved in dimethylsulfoxide(1 mL). The reaction was stirred at room temperature overnight. Themixture was purified on RP-HPLC (C18, 0.1% trifluoroacetic acid inacetonitrile/water=15-50%) to affordrac-(5aR,6S,7R,8S,8aR)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(Cpd. No. 227F, trifluoroacetic acid salt) as a white solid. Yield: 17mg, 61%; MS (ESI) m/z 526.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.79 (s,1H), 8.40 (d, J=2.0 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.8 Hz,2H), 7.23 (d, J=8.7 Hz, 2H), 7.16 (d, J=1.8 Hz, 1H), 7.15 (d, J=1.8 Hz,2H), 6.98-6.95 (m, 2H), 6.78 (s, 1H), 4.44 (d, J=7.1 Hz, 1H), 3.77-3.63(m, 1H), 3.23 (t, J=11.9 Hz, 2H), 3.01 (dd, J=14.4, 7.3 Hz, 1H), 2.93(d, J=4.5 Hz, 3H), 2.86 (d, J=4.5 Hz, 3H).

Example 228Rac-(5aR,6S,7R,8S,8aR)-3-chloro-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(Cpd. No. 228F)

Synthesis ofrac-(5aR,6S,7R,8S,8aR)-3-chloro-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(Cpd. No. 228F)

A suspension ofrac-(5aR,6S,7R,8S,8aR)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(1, trifluoroacetic acid salt, 11 mg, 0.021 mmol), zinc (1 mg, 0.011mmol) and zinc cyanide (8 mg, 0.067 mmol) in N,N-dimethylformamide (0.5mL) and water (0.05 mL) was purged with argon for 5 min. Dppf (1 mg,0.002 mmol) and tris(dibenzylideneacetone)dipalladium(0) (1 mg, 0.001mmol) were added. The reaction was microwaved at 120° C. for 0.5 h. Themixture was filtered through a pad of celite and purified via RP-HPLC(C18, 0.1% trifluoroacetic acid in acetonitrile/water=15-45%) to affordrac-(5aR,6S,7R,8S,8aR)-3-chloro-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile(Cpd. No. 228F, trifluoroacetic acid salt) as a white solid. Yield: 2.5mg, 25%; MS (ESI) m/z 471.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.05 (s,1H), 8.42 (d, J=2.0 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.7 Hz,2H), 7.49 (d, J=8.5 Hz, 2H), 7.17-7.11 (m, 3H), 7.02-6.96 (m, 2H), 6.88(s, 1H), 4.53 (d, J=7.1 Hz, 1H), 3.85-3.72 (m, 1H), 3.29-3.17 (m, 2H),3.03 (dd, J=14.4, 7.7 Hz, 1H), 2.94 (d, J=4.6 Hz, 3H), 2.85 (d, J=4.6Hz, 3H).

Example 229Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(Cpd. No. 229F)

Synthesis of 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one (2)

To a solution of2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one(1, 399 mg, 1.04 mmol) in N,N-dimethylacetamide (9 mL) was added sodiummethoxide (25% in methanol, 0.72 mL, 3.13 mmol) dropwise. The reactionwas stirred at 100° C. for 2 h. The resulting mixture was cooled to roomtemperature and quenched via the addition of saturated ammonium chloridesolution. The precipitate was filtered, washed with water and driedunder vacuum to afford2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one(2) as a yellow solid. Yield: 226 mg, 57%; MS (ESI) m/z 380.1[M+1]⁺.

Synthesis of rac-methyl(3S,4S,5R)-2-(4-bromophenyl)-5,10,10-trihydroxy-6,8-dimethoxy-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate(3)

2-(4-Bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one(2, 80 mg, 0.21 mmol) and methyl cinnamate (2a, 343 mg, 2.12 mmol) weredissolved in chloroform (3.5 mL) and trifluoroethanol (2.8 mL). Thereaction mixture was stirred vigorously and irradiated with 450 W UVlight at 0° C. for 2 h. The reaction mixture was concentrated andpurified via column chromatography (silica, ethyl acetate/hexanes=0-5%then 100%) to remove the cinnamate. The crude was used directly for thenext step. Yield: 130 mg, crude; MS (ESI) m/z 540.2[M+1]⁺.

Synthesis of rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(4)

Sodium methoxide (25% in methanol, 0.16 mL, 0.70 mmol) was added to astirred solution of rac-methyl(3S,4S,5R)-2-(4-bromophenyl)-5,10,10-trihydroxy-6,8-dimethoxy-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate(3, 130 mg, 0.23 mmol) in methanol (4 mL) at room temperature. Thereaction mixture was heated at 60° C. for 40 min and then the solventwas removed. The residue was partitioned between saturated aqueousammonium chloride and dichloromethane. The organics were combined, driedover magnesium sulfate, filtered and concentrated to afford the crudeproduct. Yield: 126 mg, crude; MS (ESI) m/z 540.2[M+1]⁺.

Synthesis of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(5)

To a stirred solution of rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(126 mg, 0.23 mmol) in acetonitrile (4 mL) at room temperature was addedacetic acid (0.13 mL, 2.33 mmol) and then sodium triacetoxyborohydride(247 mg, 1.17 mmol). The reaction was stirred at room temperature for 40min. Saturated aqueous ammonium chloride (30 mL) was added slowly andthe resulting mixture was partitioned between water and dichloromethane.The organics were combined, dried over magnesium sulfate, filtered andconcentrated. The crude was purified via column chromatography (silica,ethyl acetate/hexanes=0-45%) to afford rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylateas a yellow solid. Yield: 74 mg, 58%; MS (ESI) m/z 542.1[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (6)

To a solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(68 mg, 0.12 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) wasadded 2 M lithium hydroxide solution (2 mL, 4 mmol). The reaction wasstirred at room temperature for 2 h. The reaction was acidified with 1 Mhydrochloric acid. The mixture was extracted with water anddichloromethane. The combined organics were dried over magnesiumsulfate, filtered and concentrated. The crude was used directly for nextstep. Yield: 71 mg, crude; MS (ESI) m/z 530.2[M+1]⁺.

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(Cpd. No. 229F)

To a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (71 mg, 0.13 mmol) in N,N-dimethylformamide (2 mL) at roomtemperature were added HATU (54 mg, 0.14 mmol) andN,N-diisopropylethylamine (0.04 mL, 0.20 mmol). The reaction was stirredat room temperature for 15 min. Dimethylamine (2 M solution intetrahydrofuran) (0.2 mL, 0.40 mmol) was added and the reaction wasstirred at room temperature for 1 h. The reaction mixture was dilutedwith dichloromethane and washed with water. The combined organics weredried over magnesium sulfate, filtered and concentrated. The crude waspurified via column chromatography (silica, ethyl acetate/hexanes=0-90%)to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(Cpd. No. 229F) as a light yellow solid. Yield: 64 mg, 86%; MS (ESI) m/z557.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.25-7.18 (m, 2H), 7.08-6.99(m, 4H), 6.99-6.91 (m, 1H), 6.87 (dd, J=7.8, 1.4 Hz, 2H), 6.11 (s, 1H),4.70 (d, J=5.6 Hz, 1H), 4.35 (d, J=13.5 Hz, 1H), 4.13 (dd, J=13.5, 5.6Hz, 2H), 3.85 (s, 3H), 3.85 (s, 3H), 3.26 (s, 3H), 2.76 (s, 3H).

Example 230Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 230F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a, 6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No.230F)

Borane dimethyl sulfide complex (0.08 mL, 0.86 mmol) was added to astirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(48 mg, 0.086 mmol) in tetrahydrofuran (3 mL) at room temperature. Thereaction was heated at 40° C. After cooling to room temperature,methanol (3 mL) was added dropwise. The resulting clear colorlessreaction mixture was stirred vigorously and heated at 70° C. overnight.The reaction mixture was cooled to room temperature and purified viaPhenomenex Strata ion exchange column to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 230F) as a white solid. Yield: 35 mg, 75%; MS (ESI) m/z543.2[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.27-7.17 (m, 2H), 7.12-7.05(m, 3H), 7.02-6.97 (m, 1H), 6.97-6.92 (m, 2H), 6.02 (s, 1H), 5.29 (s,1H), 4.90 (s, 1H), 4.41 (s, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.66 (d,J=14.0 Hz, 1H), 3.10-3.00 (m, 1H), 2.55 (d, J=11.9 Hz, 1H), 2.19 (s,6H), 1.94 (dd, J=12.4, 3.1 Hz, 1H), 1.24 (s, 1H).

Example 2314-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 231F)

Synthesis of4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 231F)

A mixture ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(30 mg, 0.055 mmol), zinc cyanide (20 mg, 0.17 mmol) and zinc powder (4mg, 0.055 mmol) in N,N-dimethylformamide (0.50 mL) and water (0.05 mL)was purged with argon for 5 min.Tris(dibenzylideneacetone)dipalladium(0) (5 mg, 0.0055 mmol) and dppf (6mg, 0.011 mmol) were added. The reaction was microwaved at 120° C. for1.5 h. The mixture was cooled to room temperature, filtered and purifiedvia RP-HPLC (C18, acetonitrile/water=15-35%) to affordrac-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrileas a white solid. Yield: 11 mg, 41%; The enantiomers were separated bychiral SFC [CHIRALPAK IG (4.6×250)mm, 5μ] in CO₂/MeOH/TEA(60:40:0.2),Peak 1 (Cpd. No. 231F, 1.56 g), Rt=1.958 min, ee: 99.74%, [α]D −38.8° (c0.25, CHCl₃); MS (ESI) m/z 488.20[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 7.49(d, J=8.32 Hz, 2H), 7.34 (d, J=8.36 Hz, 2H), 7.08-7.04 (m, 2H),7.00-6.95 (m, 3H), 6.04 (s, 1H), 5.40 (s, 1H), 5.03 (bs, 1H), 4.42 (d,J=3.8 Hz, 1H), 3.84 (s, 6H), 3.73 (d, J=14.0 Hz, 1H), 3.14-3.08 (m, 1H),2.58-2.56 (m, 1H), 2.20 (s, 6H), 1.96 (d, J=10.7 Hz, 1H). Peak-2 (1.55g), R_(t)=3.90 min, ee: 99.66%, [α]_(D) +34.50 (c 0.20, CHCl₃); MS (ESI)m/z 488.20[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 7.49 (d, J=8.48 Hz, 2H),7.34 (d, J=8.48 Hz, 2H), 7.08-7.04 (m, 2H), 7.00-6.95 (m, 3H), 6.04 (s,1H), 5.40 (s, 1H), 5.03 (bs, 1H), 4.42 (d, J=4.12 Hz, 1H), 3.84 (s, 6H),3.73 (d, J=14.12 Hz, 1H), 3.14-3.08 (m, 1H), 2.58-2.56 (m, 1H), 2.20 (s,6H), 1.97 (d, J=9.68 Hz, 1H).

Example 232Rac-4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 232F)

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-N,N-diethyl-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(2)

HATU (19 mg, 0.050 mmol) was added to a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (25 mg, 0.047 mmol) in N,N-dimethylformamide (2 mL) at roomtemperature. After 2 min, N,N-diisopropylethylamine (0.01 mL, 0.071mmol) was added. The reaction was stirred for 15 min at roomtemperature. Diethylamine (0.15 mL, 1.42 mmol) was added and thereaction was stirred at room temperature overnight. The reaction mixturewas diluted with dichloromethane and washed with water. The combinedorganics were dried over magnesium sulfate, filtered, concentrated on arotary evaporator, and purified via column chromatography (silica, ethylacetate/hexanes=0-90%) to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-N,N-diethyl-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(2) as a light yellow solid. Yield: 30 mg, 100%; MS (ESI) m/z585.4[M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((diethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3)

Borane dimethyl sulfide complex (0.05 mL, 0.51 mmol) was added to astirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-N,N-diethyl-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(2, 30 mg, 0.051 mmol) in tetrahydrofuran (3 mL) at room temperature.The reaction mixture was heated at 40° C. for 5 h. After cooling to roomtemperature, methanol (3 mL) was added dropwise. The resulting clearcolorless reaction mixture was stirred vigorously and heated at 70° C.overnight. The reaction mixture was cooled to room temperature andpurified via Phenomenex Strata ion exchange column to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((diethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3) as a light yellow solid. Yield: 35 mg, 100%; MS (ESI) m/z569.4[M+1]⁺;

Synthesis ofrac-4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 232F)

A mixture ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((diethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(10 mg, 0.018 mmol), zinc cyanide (6 mg, 0.053 mmol) and zinc powder (1mg, 0.018 mmol) in N,N-dimethylformamide (0.50 mL) and water (0.050 mL)was purged with argon for 5 min.Tris(dibenzylideneacetone)dipalladium(0) (2 mg, 0.0018 mmol) and dppf (2mg, 0.0035 mmol) were added. The reaction was microwaved at 120° C. for2 h. The mixture was cooled to room temperature, filtered and purifiedvia RP-HPLC (C18, acetonitrile/water=15-35%) to affordrac-4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 232F) as a white solid. Yield: 4 mg, 44%; MS (ESI) m/z516.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (s, 1H), 7.54 (d, J=8.8Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.15-6.94 (m, 5H), 6.11 (s, 1H), 5.58(s, 1H), 5.33 (d, J=6.8 Hz, 1H), 4.65-4.56 (m, 1H), 3.87 (s, 3H), 3.86(s, 3H), 3.80 (d, J=13.9 Hz, 1H), 3.52-3.42 (m, 2H), 3.19-3.08 (m, 2H),2.71-2.62 (m, 1H), 1.19 (t, J=7.1 Hz, 6H).

Example 2334-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl(2,2,2-trifluoroethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 233F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 0.65 g, 1.3 mmol) in dichloromethane (10.0 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.3 g, 1.9 mmol),hydroxybenzotriazole (0.26 g, 1.9 mmol) and N,N-diisopropylethylamine(0.7 mL, 3.9 mmol) were added at 0° C. and stirred the mixture for 5min. Methylamine hydrochloride (0.26 g, 3.9 mmol) was then added at sametemperature and the reaction was stirred at room temperature for 5 h.After completion, reaction mass was diluted with dichloromethane (20 mL)and washed with cold water. The organic layer was separated and driedover anhydrous sodium sulphate, filtered and concentrated under reducedpressure. The crude product was purified by Combi-flash (12 g RediSepcolumn) using 30% ethyl acetate in hexanes as eluent. The desiredfraction were concentrated to afford rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(2) as white solid. Yield: 0.6 g, 90%; MS (ESI) m/z 511.36 [M+1]⁺, UPLC:97.28%.

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methylamino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(2, 0.6 g, 1.2 mmol) in tetrahydrofuran (30 mL), borane dimethylsulfide(1.0 ml, 11.7 mmol) was added at 0° C. The reaction mixture was heatedat 60° C. for 3 h. After completion, reaction mass was quenched withmethanol at 0° C. and then heated at 80° C. for 16 h. The solvents wereconcentrated and the solid obtained was dried to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methylamino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3) as white solid. Yield: 0.45 g, 77%; MS (ESI) m/z 496.37[M−1]⁻, UPLC:93.46%

Synthesis ofrac-N-(((4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methyl)-2,2,2,2-trifluoro-N-methylacetamide(4)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methylamino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3, 0.8 g, 1.6 mmol) in dichloromethane (5.0 mL), trifluoro aceticanhydride (0.4 g, 1.9 mmol), and triethylamine (0.7 mL, 4.8 mmol) wereadded at 0° C. and stirred the mixture for 5 minute and then reactionwas stirred at room temperature for 30 min. After completion, reactionmixture was diluted with dichloromethane (20 mL) and washed with coldwater. The organic layer was separated and dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure. The crudeproduct was purified by Combi-flash (12 g RediSep column) using 30%ethyl acetate in hexanes as eluent. The desired fractions wereconcentrated to affordrac-N-(((4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methyl)-2,2,2-trifluoro-N-methylacetamide(4) as yellow solid. Yield: 0.4 g, 43%; MS (ESI) m/z 579.20[M+1]⁺, UPLC:82.36%.

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methyl(2,2,2-trifluoroethyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(5)

To a solution ofrac-N-(((4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methyl)-2,2,2-trifluoro-N-methylacetamide(4, 0.2 g, 0.3 mmol) in tetrahydrofuran (20 mL), borane dimethylsulfide(0.3 ml, 3.7 mmol) was added at 0° C. The reaction mixture was heated at60° C. for 6 h. After completion, reaction mass was quenched withmethanol at 0° C. and then heated at 90° C. for 16 h. The solvents wereconcentrated and the solid obtained was dried to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methyl(2,2,2-trifluoroethyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(5) as yellow solid. Yield: 0.15 g, 77%; MS (ESI) m/z 579.2[M+1]⁺, UPLC:89.22%.

Synthesis of4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl(2,2,2-trifluoroethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 233F)

To a mixture ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methyl(2,2,2-trifluoroethyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(5, 0.15 g, 0.26 mmol) in N,N-dimethylformamide (10.0 mL) at roomtemperature, zinc cyanide (182 mg, 1.55 mmol) and zinc (3 mg, 0.05 mmol)were added at room temperature and mixture was degassed with argon for15 min. 1,1′-Bis(diphenylphosphino) ferrocene (4.0 mg, 0.008 mmol) andtris(dibenzylideneacetone)dipalladium (7.0 mg, 0.08 mmol) were added tothe reaction mixture and degassing was continued for another 5 min. Thereaction mixture was heated at 140° C. for 16 h. After completion, thereaction was cooled to room temperature and passed through celite bed.The filtrate was concentrated and treated with ice-cold water, the solidprecipitated was filtered. The crude solid was purified by Combi-flash(12 g RediSep column) using 30% ethyl acetate in hexanes as eluent. Thenit was submitted for reverse prep HPLC. The desired fractions werelyophilized to affordrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl(2,2,2-trifluoroethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.10 g, 73%. The enantiomers were separated bychiral preparative HPLC [chiralpak IB (4.6×250) mm] usingn-Hexane/EtOH(90/10) (v/v) Mobile phase. Peak 1 (21 mg), [α]_(D) −13.0°(c 0.2, CHCl₃), R_(t)=12.65 min, ee>99%. MS (ESI) m/z 526.45[M+1]⁺;UPLC: 99.29%; 1H NMR (400 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.97 (s, 1H),7.49 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.09-6.97 (m, 5H), 5.72(s, 1H), 5.11 (d, J=5.7 Hz, 1H), 4.59 (t, J=5.0 Hz, 1H), 3.88 (s, 3H),3.77 (d, J=14.0 Hz, 1H), 3.42-2.75 (m, 4H), 2.46 (s, 3H), 2.39 (d,J=11.0 Hz, 1H). Peak 2 (Cpd. No. 233F, 22 mg), [α]_(D) +14.5° (c 0.2,CHCl₃), R_(t)=17.019 min, ee>99%. MS (ESI) m/z 526.42[M+1]⁺; UPLC:99.42%; ¹H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.97 (s, 1H), 7.49 (d,J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.09-6.97 (m, 5H), 5.71 (s, 1H),5.11 (d, J=5.4 Hz, 1H), 4.50 (t, J=5.0 Hz, 1H), 3.88 (s, 3H), 3.77 (d,J=14.0, 1H), 3.42-2.73 (m, 4H), 2.46 (s, 3H), 2.39 (d, J=11.5 Hz, 1H).

Example 234Rac-(4bR,5R,7S,7aR)-7a-(4-(aminomethyl)phenyl)-5-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 234F)

Synthesis ofrac-(4bR,5R,7S,7aR)-7a-(4-(aminomethyl)phenyl)-5-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 234F)

To a solution ofrac-4-((4bR,5R,7S,7aR)-4b-hydroxy-5-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(1, 0.050 g, 0.120 mmol) in methanol (1 mL) at 0° C., was added nickel(II) chloride hexa hydrate (0.028 g, 0.12 mmol) followed by sodiumborohydride (0.0091 g, 0.24 mmol) at the same temperature. The reactionwas stirred for 2 h at room temperature. After completion, the reactionmass was quenched with ice water extracted with ethyl acetate and washedwith cold water. The organic layer was separated and dried overanhydrous sodium sulphate, filtered and concentrated to give crude. Thecrude was purified by reverse phase prep-HPLC and desired fractions werelyophilized to affordrac-(4bR,5R,7S,7aR)-7a-(4-(aminomethyl)phenyl)-5-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 234F) as white solid. Yield: 0.005 g, 10% (racemic); MS (ESI)m/z 419.29[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 8.13 (s, 1H), 8.05 (s, 1H),7.16 (d, J=8.2 Hz, 2H), 7.09-7.02 (m, 5H), 7.00 (d, J=7.3 Hz, 2H), 5.23(s, 1H), 4.59 (bs, 1H), 4.05-4.02 (dd, J=6.8, 10.8 Hz, 1H), 3.95 (s,3H), 3.88 (t, J=10.5 Hz, 1H), 3.58 (s, 2H), 2.77 (m, 1H), 2.42 (d,J=14.9 Hz, 1H), 2.22 (m, 1H).

Example 235Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone(Cpd. No. 235F)

Synthesis ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone(Cpd. No. 235F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.0 g, 2.0 mmol) in N,N-dimethylformamide (20 mL), HATU (2.29g, 6.0 mmol) and N,N-diisopropylethylamine (1.80 ml, 10.0 mmol) wereadded at 0° C. and stirred the mixture for 5 min.2-oxa-6-azaspiro[3.3]heptane oxalate (2, 1.44 g, 5.0 mmol) was thenadded and the reaction mixture was stirred for 2 h at room temperature.After completion, reaction mass was diluted with ethyl acetate andwashed with cold water. The organic layer was dried over anhydroussodium sulphate, filtered and concentrated to give crude product. Thecrude product was purified by combi-flash (12 g, RedisSep column) using6% methanol in dichloromethane as eluent. The desired fractions wereconcentrated to affordrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone(Cpd. No. 235F) as white solid. Yield: 0.85 g, 73%; MS (ESI) m/z579.25[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (s, 1H), 7.98 (s, 1H),7.20 (d, J=8.6 Hz, 2H), 7.04-7.01 (m, 4H), 6.97-6.90 (m, 3H), 5.68 (s,1H), 5.16 (d, J=5.3 Hz, 1H), 4.77 (t, J=6.8 Hz, 2H), 4.73-4.70 (m, 2H),4.67 (d, J=5.4 Hz, 2H), 4.49 (d, J=8.9 Hz, 1H), 4.33 (d, J=13.6 Hz, 1H),3.97 (s, 2H), 3.87 (s, 3H), 3.83-3.79 (dd, J=5.2 Hz, 13.9 Hz, 1H).

Example 236Rac-4-((4bS,5R,6S,7S,7aR)-6-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 236F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-6-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (2)

To a solution ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone(1, 0.89 g, 1.0 mmol) in tetrahydrofuran (15 mL), borane dimethylsulfide(0.23 ml, 3.0 mmol) was added at 0° C. The reaction mixture was stirredfor 3 h at room temperature. After completion, reaction mass wasquenched with methanol at 0° C. and then heated at 60° C. for 4 h. Thesolvents were concentrated to give crude product. The crude product waspurified by combi-flash (4 g, RediSep column) using 7% methanol indichloromethane as eluent. The desired fractions were concentrated toaffordrac-(4bS,5R,6S,7S,7aR)-6-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 0.55 g, 64%; MS (ESI) m/z565.72[M+1]Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-6-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 236F)

To a mixture ofrac-(4bS,5R,6S,7S,7aR)-6-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.55 g, 0.97 mmol) in N,N-dimethylformamide (10.0 mL) at roomtemperature, zinc cyanide (670 mg, 5.89 mmol) and zinc dust (62 mg, 0.97mmol) were added at room temperature and degassed the mixture with argonfor 15 min. 1,1′-Bis(diphenylphosphino) ferrocene (139 mg, 0.19 mmol)and tris(dibenzylideneacetone)dipalladium (266 mg, 0.29 mmol) were addedto the reaction mixture and degassing was continued for another 5 min.The reaction mixture was heated at 140° C. for 2.5 h. After completion,the reaction was cooled to room temperature and passed through celitebed. The filtrate was diluted with ethyl acetate and washed with water.The organic layer was separated, dried over anhydrous sodium sulphateand concentrated under reduced pressure to give the crude. The crudeproduct was purified by reverse phase prep HPLC. The desired fractionswere lyophilized to affordrac-4-((4bS,5R,6S,7S,7aR)-6-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.15 g, 30%. The enantiomers were separated bychiral preparative HPLC [chiralpak IA (4.6×250) mm] usingn-Hexane/EtOH=50/50 (v/v) Mobile phase. Peak 1 (Cpd. No. 236F, 40 mg);[α]_(D) −99.1° (c 0.29, CHCl₃), R_(t)=5.661 min, ee 99.90%. MS (ESI) m/z512.28[M+1]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.96 (s, 1H),7.48 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 7.09-7.06 (m, 2H),7.01-6.97 (m, 3H), 5.72 (s, 1H), 5.40 (brs, 1H), 4.58 (d, J=3.2 Hz, 4H),4.44 (d, J=2.5 Hz, 1H), 3.87 (s, 3H), 3.78 (d, J=14.1 Hz, 1H), 3.29 (s,4H), 2.94 (s, 1H), 2.69-2.49 (m, 1H), 2.25-2.17 (m, 1H). Peak-2 (34 mg);[α]_(D) +23.0° (c 0.259, CHCl₃), R_(t)=22.48 min, ee 99.30%. MS (ESI)m/z 512.24 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (s, 1H), 7.96 (s,1H), 7.48 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 7.09-7.06 (m, 2H),7.01-6.97 (m, 3H), 5.72 (s, 1H), 5.39 (bs, 1H), 4.60-4.56 (m, 4H), 4.44(d, J=2.5 Hz, 1H), 3.87 (s, 3H), 3.78 (d, J=14.1 Hz, 1H), 3.29 (s, 4H),2.94 (s, 1H), 2.69-2.50 (m, 1H), 2.25-2.17 (m, 1H).

Example 237Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-N-(oxetan-3-yl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 237F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-N-(oxetan-3-yl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 237F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.0 g, 2.0 mmol) in N,N-dimethylformamide (10 mL),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (2.29 g, 6.0 mmol) and N,N-diisopropylethylamine(1.80 ml, 10.0 mmol) were added at 0° C. and stirred the mixture for 5min. N-methyloxetan-3-amine (2, 1.44 g, 5.0 mmol) was then added and thereaction mixture was stirred for 2 h at room temperature. Aftercompletion, reaction mixture was diluted with ethyl acetate and washedwith cold water. The organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated to give crude product. The crudeproduct was purified by combi-flash (12 g, RediSep column) using 6%methanol in dichloromethane as eluent. The desired fractions wereconcentrated to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-N-(oxetan-3-yl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 237F) as white solid. Yield: 0.94 g, 83%; MS (ESI) m/z567.25[M+1]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.99 (s, 1H),7.22-7.20 (m, 2H), 7.12-7.07 (m, 2H), 7.04-7.01 (m, 2H), 6.96-6.86 (m,3H), 5.71 (d, J=11.3 Hz, 1H), 5.24 (d, J=5.3 Hz, 1H), 5.09-5.06 (m, 1H),4.97-4.75 (m, 2H), 4.63-4.53 (m, 3H), 4.36 (d, J=13.6 Hz, 1H), 4.25-4.20(m, 1H), 3.87 (s, 3H), 3.43 (s, 2H), 2.96 (s, 1H).

Example 238Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl(oxetan-3-yl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 238F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methyl(oxetan-3-yl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-N-(oxetan-3-yl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 0.55 g, 0.97 mmol) in tetrahydrofuran (15 mL), borane dimethylsulfide (0.18 ml, 1.94 mmol) was added at 0° C. The reaction mixture wasstirred for 3 h at room temperature. After completion, reaction mixturewas quenched with methanol at 0° C. and then heated at 60° C. for 4 h.The solvents were concentrated to give crude product. The crude productwas purified by combi-flash (4 g, RediSep column) using 0-7% methanol indichloromethane as eluent. The desired fractions were concentrated toaffordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methyl(oxetan-3-yl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 0.16 g, 29%; MS (ESI) m/z 553.12[M+1]⁺.

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl(oxetan-3-yl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 238F)

To a mixture ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methyl(oxetan-3-yl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.31 g, 0.56 mmol) in N,N-dimethylformamide (5.0 mL) at roomtemperature, zinc cyanide (0.656 g, 5.61 mmol) and zinc (0.003 g, 0.05mmol) were added and the mixture was degassed with argon for 15 min.1,1′-Bis(diphenylphosphino) ferrocene (0.093 g, 0.168 mmol) andtris(dibenzylideneacetone)dipalladium (0.154 g, 0.168 mmol) were addedto the reaction mixture and degassing was continued for another 5 min.The reaction mixture was heated at 130° C. for 2.5 h. After completion,the reaction was cooled to room temperature and passed through celitebed. The filtrate was diluted with ethyl acetate and washed with water.The organic layer was separated, dried over anhydrous sodium sulphateand concentrated under reduced pressure to give the crude product. Thecrude product was purified by combi-flash (12 g, RediSep column) using0-10% methanol in dichloromethane as eluent. The product obtained wasfurther purified by reverse phase prep HPLC. The desired fractions werelyophilized to affordrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl(oxetan-3-yl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.036 g, 13%. The enantiomers were separated bychiral preparative HPLC [chiralpak IA (4.6×250) mm] usingn-Hexane/EtOH=70/30 (v/v) Mobile phase. Peak 1 (9 mg); R_(t)=7.54,ee>99%; MS (ESI) m/z 500.33[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (s,1H), 7.97 (s, 1H), 7.48 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H),7.09-7.05 (m, 2H), 7.0-6.98 (m, 3H), 5.76 (s, 1H), 5.22 (d, J=5.7 Hz,1H), 4.50-4.45 (m, 3H), 4.43-4.36 (m, 2H), 3.89 (s, 3H), 3.79 (d, J=14.1Hz, 1H), 3.41 (t, J=5.92 Hz, 1H), 3.19 (bs, 1H), 2.56 (bs, 1H) 2.20 (s,3H), 1.84 (d, J=11.6 Hz, 1H); Peak 2 (Cpd. No. 238F, 8 mg); R_(t)=11.54,ee>99%; MS (ESI) m/z 500.30[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (s,1H), 7.97 (s, 1H), 7.48 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H),7.09-7.05 (m, 2H), 7.0-6.98 (m, 3H), 5.76 (s, 1H), 5.22 (d, J=5.3 Hz,1H), 4.48-4.42 (m, 3H), 4.40-4.36 (m, 2H), 3.89 (s, 3H), 3.80 (d, J=14.2Hz, 1H), 3.41 (t, J=6.7 Hz, 1H), 3.19 (t, J=14.0 Hz, 1H), 2.56 (brs,1H), 2.20 (s, 3H), 1.84 (d, J=11.2 Hz, 1H).

Example 239Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(oxetan-3-yl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 239F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(oxetan-3-yl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 239F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.5 g, 3.0 mmol) in N,N-dimethylformamide (20 mL),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (3.43 g, 9.0 mmol) and N,N-diisopropylethylamine (2.7 ml, 15.0 mmol) were added at 0° C. and stirred themixture for 5 min. oxetan-3-amine hydrochloride (2, 0.82 g, 7.5 mmol)was then added and the reaction mixture was stirred for 4 h at roomtemperature. After completion, reaction mass was diluted with ethylacetate and washed with cold water. The organic layer was dried overanhydrous sodium sulphate, filtered and concentrated to give crudeproduct. The crude product was purified by Combi-flash (12 g RediSepcolumn) using 0-3% methanol in dichloromethane as eluent. The productobtained was repurified by reverse phase prep HPLC. The desiredfractions were lyophilized to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(oxetan-3-yl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 239F) as brown solid. Yield: 1.1 g, 66%; MS (ESI) m/z553.19[M+1]⁺. UPLC: 99.82%, 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J=6.2Hz, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.23 (d, J=8.6 Hz, 2H), 7.07-6.94(m, 7H), 5.67 (s, 1H), 5.14 (d, J=4.7 Hz, 1H), 4.71-4.64 (m, 4H), 4.42(t, J=5.8 Hz, 1H), 4.34-4.31 (m, 2H), 3.87 (s, 3H), 3.84 (d, J=4.8 Hz,1H).

Example 240Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((oxetan-3-ylamino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 240F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((oxetan-3-ylamino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(oxetan-3-yl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 1.0 g, 1.8 mmol) in tetrahydrofuran (30 mL), borane dimethylsulfide(0.5 ml, 5.4 mmol) was added at 0° C. Then reaction mixture was stirredat room temperature for 16 h. After completion, reaction mass wasquenched with methanol at 0° C. and then heated at 80° C. for 6 h. Thesolvents were concentrated and the residue was purified by flash columnchromatography by eluting with gradient of 1-5% methanol indichloromethane. The fractions containing desired product wasconcentrated and dried under vacuum to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((oxetan-3-ylamino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as brown solid. Yield: 0.12 g, 12%; MS (ESI) m/z 539.37[M+1]⁺, UPLC:50.27% Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((oxetan-3-ylamino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 240F)

To a mixture ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((oxetan-3-ylamino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.12 g, 0.2 mmol) in N,N-dimethylformamide (5.0 mL) at roomtemperature, zinc cyanide (26 mg, 2.2 mmol) and zinc (14 mg, 0.2 mmol)were added at room temperature and degassed the mixture with argon for15 min. 1,1′-Bis(diphenylphosphino) ferrocene (36.0 mg, 0.06 mmol) andtris(dibenzylideneacetone)dipalladium (61.0 mg, 0.06 mmol) were added tothe reaction mixture and degassing was continued for another 5 min. Thereaction mixture was heated at 140° C. for 3 h. After completion, thereaction mass was cooled to room temperature and passed through celitebed. Filtrate was concentrated and treated with ice-cold water, thesolid precipitated was filtered. The crude product was purified byCombi-flash (12 g RediSep column) using 30% ethyl acetate: hexanes aseluent. The product obtained was repurified by reverse phase prep HPLC.The desired fractions were lyophilized to affordrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((oxetan-3-ylamino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 240F) as white solid. Yield: 0.02 g, 18%, MS (ESI) m/z486.24[M+1]⁺; UPLC: 94.57%; 1H NMR (400 MHz, DMSO-d₆) δ 8.03 (s, 1H),7.96 (s, 1H), 7.46 (d, J=8.34 Hz, 2H), 7.34 (d, J=8.36 Hz, 2H),7.05-6.94 (m, 5H), 5.69 (s, 1H), 5.30 (s, 1H), 4.59-4.52 (m, 3H),4.29-4.22 (m, 2H), 3.87 (s, 3H), 3.80-3.70 (m, 2H), 3.06 (d, J=3.72 Hz,1H), 2.53-1.78 (m, 2H), 1.78 (s, 1H).

Example 241Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 241F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-((1-methyl-1H-pyrazol-5-yl)methyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide.(Cpd. No. 241F)

To the solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.00 g, 2.01 mmol) in N,N-dimethylformamide (5 mL) at 0° C.,HATU (1.14 g, 3.01 mmol) and N,N-diisopropylethylamine (1.04 ml, 6.02mmol) were added and the mixture was stirred for 5 min.(1-methyl-1H-pyrazol-5-yl)methanamine (2, 0.27 ml, 3.01 mmol) was addedat the same temperature and the reaction was stirred for 16 h at roomtemperature. After completion, the reaction mixture was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel (100-200 mesh size) column chromatography using 0-3% methanolin dichloromethane as eluent. The desired fractions were concentrated toaffordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-((1-methyl-1H-pyrazol-5-yl)methyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 241F) as white solid. Yield: 0.85 g, 83%; MS (ESI) m/z591.41[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆); ¹H NMR (400 MHz, DMSO-d₆) 8.62(t, J=5.2 Hz, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.24 (d, J=9.0 Hz, 3H),7.10-7.04 (m, 4H), 7.01-6.96 (m, 3H), 6.06 (s, 1H), 5.86 (s, 1H), 5.27(bs, 1H), 4.63 (d, J=4.4 Hz, 1H), 4.40 (d, J=14.0 Hz, 1H), 4.35-4.21 (m,2H), 3.97 (d, J=4.6 Hz, 1H), 3.91 (s, 3H), 3.61 (s, 3H).

Example 242Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 242F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-((1-methyl-1H-pyrazol-5-yl)methyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 0.85 g, 1.43 mmol) in dry tetrahydrofuran (30 ml) at 0° C., boranedimethyl sulphide complex (1.36 ml, 14.37 mmol) was added drop wise overa period of 5 min. The reaction mixture was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mixture was quenched with methanol at 0° C. and heated toreflux for 24 h. After completion, solvent was removed under reducedpressure and the residue was purified over a plug of silica gel (100-200mesh size) using 5% methanol in dichloromethane as a eluent. The desiredfractions were concentrated under reduced pressure to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as a white solid. Yield: 0.65 g, 72%; MS (ESI) m/z 577.28[M+1]⁺.

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 242F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.65 g, 1.12 mmol) in N,N-dimethylformamide (10 mL), zinc cyanide(1.3 g, 11.2 mmol) and zinc dust (0.0085 g, 0.131 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.012 g, 0.021 mmol) andtetrakis(triphenylphosphine)palladium (0.693 g, 0.6 mmol) were added tothe reaction mixture, degassed for additional 5 min and mixture washeated at 140° C. for 8 h. After completion, the reaction mixture wasdiluted with ethyl acetate and washed with cold water. The organic layerwas separated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel (100-200 mesh size) column chromatography using 2-3% methanolin dichloromethane as eluent. The desired fractions were concentrated toaffordrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 242F) as a white solid. Yield: 0.59 g, 54% (racemic); Theenantiomers were separated by chiral HPLC [Chiralpak IA (4.6×250) mm,5μ] in Hexane/Ethanol=40/60 (v/v). Peak 1 (70 mg), [α]_(D) +24.2° (c0.252, CHCl₃), R_(t)=5.47 min, ee: 99.60%; MS (ESI) m/z 524.28[M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) 8.05 (s, 1H), 7.98 (s, 1H), 7.49 (d, J=8.52 Hz,2H), 7.36 (d, J=8.40 Hz, 2H), 7.25 (bs, 1H), 7.05-7.03 (m, 2H),6.98-6.92 (m, 4H), 6.09 (s, 1H), 5.70 (s, 1H), 5.29 (bs, 1H), 4.55 (s,1H), 3.88 (s, 4H), 3.84-3.69 (m, 7H). 3.17 (bs, 1H). Peak-2 (64 mg),[α]_(D) −21.0° (c 0.27, CHCl₃), R_(t)=10.36 min, ee:99.52%; MS (ESI) m/z524.28[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 8.05 (s, 1H), 7.98 (s, 1H),7.53-7.48 (m, 2H), 7.36 (d, J=7.56 Hz, 2H), 7.25 (bs, 1H), 7.05-7.03 (m,2H), 6.98 (bs, 4H), 6.09 (s, 1H), 5.70 (s, 1H), 5.28 (bs, 1H), 4.55 (s,1H), 3.89 (s, 4H), 3.80-3.69 (m, 7H). 3.17 (bs, 1H).

Example 2434-((4bS,5R,6S,7S,7aR)-6-((tert-butyl(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 243F)

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-6-((tert-butylamino)methyl)-5-((tert-butyldimethylsilyl)oxy)-4b-hydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(2)

To a solution ofrac-4-((4bS,5R,6S,7S,7aR)-6-((tert-butylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(1, 0.41 g, 0.84 mmol) in dichloromethane (10 mL) at 0° C., 2,6-Lutidine(0.24 mL, 2.10 mmol) and tert-Butyldimethylsilyltrifluoromethanesulfonate (0.30 mL, 1.26 mmol) were added and reactionmixture was stirred for 1 h at room temperature. The reaction wasmonitored by TLC. After completion, the crude reaction mixture was usedas such for next step.

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-6-((tert-butyl(meh)amino)methyl)-4b,5-dihy)b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 243F)

A solution ofrac-4-((4bS,5R,6S,7S,7aR)-6-((tert-butylamino)methyl)-5-((tert-butyldimethylsilyl)oxy)-4b-hydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(2) (obtained from previous step) in dichloromethane (10 mL) at 0° C.,p-formaldehyde (0.100 g, 3.36 mmol), sodium acetate (0.68 g, 0.84 mmol)and sodium triacetoxyborohydride (0.711 g, 3.36 mmol) were added andreaction mixture was stirred at room temperature for 2 h. Aftercompletion, the reaction mixture was diluted with water, neutralizedwith sodium bicarbonate solution and extracted with 10% methanol indichloromethane. The organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated to give crude. The crude waspurified by column chromatography using silica gel (100-200 mesh) and0-6% 7M methanolic ammonia in dichloromethane as eluent. The desiredfractions were concentrated under reduced pressure to affordrac-4-((4bS,5R,6S,7S,7aR)-6-((tert-butyl(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.230 g, 55%; MS (ESI) m/z 500.52[M+1]⁺. Theenantiomers were separated by chiral HPLC [Chiralpak IC (4.6×250)mm,5μ], 0.1% TEA in n-Hexane/IPA=70/30 (v/v) Peak 1 (50 mg), [α]_(D) +33.2°(c 0.28, CHCl₃), R_(t)=7.94 min, ee: 99.88%; MS (ESI) m/z 500.37[M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) □ 8.04 (s, 1H), 7.96 (s, 1H), 7.48 (d, J=8.5Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.08-7.05 (m, 2H), 7.02-6.96 (m, 3H),5.72 (s, 1H), 5.32 (bs, 1H), 4.50 (s, 1H), 3.93 (s, 1H), 3.87 (s, 3H),3.13 (bs, 1H), 2.73 (bs, 1H), 2.25-2.19 (m, 3H), 1.25-1.22 (m, 1H), 0.94(s, 9H). Peak-2 (Cpd. No. 243F, 52 mg) [α]_(D) −35.2° (c 0.25, CHCl₃),R_(t)=14.67 min, ee: 99.74%; MS (ESI) m/z 500.40[M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) D 8.04 (s, 1H), 7.96 (s, 1H), 7.48 (d, J=8.5 Hz, 2H), 7.36 (d,J=8.44 Hz, 2H), 7.08-7.05 (m, 2H), 7.02-6.98 (m, 3H), 5.72 (s, 1H), 5.32(bs, 1H), 4.50 (s, 1H), 3.93 (s, 1H), 3.87 (s, 3H), 3.13 (bs, 1H), 2.73(bs, 1H), 2.25-2.19 (m, 3H), 1.25-1.22 (m, 1H), 0.94 (s, 9H).

Example 244Rac-4-((4bS,5R,6S,7S,7aR)-6-((cyclopropylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 244F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((cyclopropylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-cyclopropyl-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 1.20 g, 22.3 mmol) in dry tetrahydrofuran (25 ml) at 0° C., boranedimethyl sulphide complex (2.1 ml, 22.3 mmol) was added drop wise over aperiod of 5 min. The reaction mass was slowly brought to roomtemperature and stirred for additional 18 h. After completion, thereaction mixture was quenched with methanol at 0° C. and heated toreflux for 3 h. After completion, solvent was removed under reducedpressure and the residue was purified over a plug of silica gel (100-200mesh size) eluting the compound with 5% methanol in dichloromethane aseluent. The desired fractions were concentrated under reduced pressureto affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((cyclopropylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 0.8 g, 68%; MS (ESI) 523.34 m/z [M+1]⁺.

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-6-((cyclopropylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 244F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((cyclopropylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.3 g, 0.57 mmol) in N,N-dimethylformamide (5 mL), zinc cyanide(0.40 g, 3.4 mmol) and zinc dust (0.0044 g, 0.068 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.0063 g, 0.011 mmol) andtris(dibenzylideneacetone)dipalladium (0.015 g, 0.017 mmol) were addedto the reaction, degassed for additional 5 min and mixture was heated at130° C. for 25 min. After completion, the reaction mass was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by silica gel(100-200 mesh size) column chromatography using 2-3% methanol indichloromethane as eluent. The product obtained was repurified byreverse phase HPLC. The desired fractions were lyophilized to affordrac-4-((4bS,5R,6S,7S,7aR)-6-((cyclopropylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 244F) as white solid. Yield: 0.004 g, 14%; MS (ESI) m/z470.35[M+1]⁺. H NMR (400 MHz, DMSO-d₆) 8.05 (s, 1H), 7.98 (s, 1H), 7.50(d, J=8.0 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.09 (t, J=6.96 Hz, 2H),7.01-6.98 (m, 3H), 5.70 (s, 1H), 5.27 (d, J=4.4 Hz, 1H), 4.51 (d, J=4.4Hz, 1H), 3.89 (s, 3H), 3.78 (d, J=14.0 Hz, 1H), 3.14 (bs, 1H), 2.74 (bs,1H), 2.69-2.59 (m, 2H), 2.10 (bs, 1H), 0.38 (bs, 2H), 0.25 (bs, 2H).

Example 245Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-cyclopropyl-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 245F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-cyclopropyl-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 245F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.5 g, 3.02 mmol) in dichloromethane (20 mL) at 0° C.,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (1.71 g, 4.52 mmol) andN,N-diisopropylethylamine (3.2 ml, 18.4 mmol) were added and the mixturewas stirred for 5 min. N-methylcyclopropanamine (0.97 g, 9.0 mmol) wasthen added at the same temperature and the reaction was stirred for 16 hat room temperature. After completion, the reaction mixture was dilutedwith dichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel (100-200 mesh size) column chromatography using 0-5% methanolin dichloromethane as eluent. The desired fractions were concentrated toafford rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-cyclopropyl-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 245F) as white solid. Yield: 1.3 g, 78%; MS (ESI) m/z551.25[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 8.11 (s, 1H), 8.01 (s, 1H), 7.28(d, J=8.4 Hz, 2H), 7.06-6.95 (m, 5H), 6.80 (d, J=7.2 Hz, 2H), 5.73 (s,1H), 5.11 (d, J=5.2 Hz, 1H), 4.94 (t, J=5.6 Hz, 1H), 4.46 (dd, J=13.7,4.7 Hz, 1H), 4.31 (d, J=13.6 Hz, 1H), 3.89 (s, 3H), 3.35 (bs, 1H), 3.20(bs, 1H), 3.02 (s, 1H), 2.73 (s, 3H), 1.33-1.23 (m, 2H).

Example 246Rac-4-((4bS,5R,6S,7S,7aR)-6-((cyclopropyl(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 246F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((cyclopropyl(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-cyclopropyl-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 1.20 g, 2.17 mmol) in dry tetrahydrofuran (20 ml) at 0° C., boranedimethyl sulphide complex (2.06 ml, 21.7 mmol) was added drop wise overa period of 5 min. The reaction mixture was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mixture was quenched with methanol at 0° C. and heated toreflux for 5 h. After completion, solvent was removed under reducedpressure and the residue was purified by silica gel (100-200 mesh size)column chromatography eluting the compound with 5% methanol indichloromethane as eluent. The desired fractions were concentrated underreduced pressure to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((cyclopropyl(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 0.8 g, 64%; MS (ESI) 538.38 m/z [M+1]⁺.

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-6-((cyclopropyl(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 246F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((cyclopropyl(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.5 g, 0.93 mmol) in N,N-dimethylformamide (5 mL), zinc cyanide(0.53 g, 4.6 mmol) and zinc dust (0.0071 g, 0.12 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.010 g, 0.019 mmol) andtris(dibenzylideneacetone)dipalladium (0.026 g, 0.028 mmol) were addedto the reaction, degassed for additional 5 min and mixture was heated at130° C. for 3 h. After completion, the reaction mixture was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel (100-200 mesh size) column chromatography using 2-3% methanolin dichloromethane as eluent. The desired fractions were concentrated toaffordrac-4-((4bS,5R,6S,7S,7aR)-6-((cyclopropyl(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 246F) as white solid. Yield: 0.08 g, 17%; MS (ESI) m/z484.34[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 8.04 (s, 1H), 7.96 (s, 1H), 7.50(d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.09 (t, J=14.8 Hz, 2H), 7.01(d, J=6.4 Hz, 3H), 5.72 (s, 1H), 5.07 (d, J=6.4 Hz, 1H), 4.43-4.41 (t,J=5.5 Hz, 1H), 3.87 (s, 3H), 3.80 (d, J=14.1 Hz, 1H), 3.25-3.22 (m, 1H),2.83 (t, J=12.2 Hz, 1H), 2.36 (s, 3H), 2.27 (d, J=10.4 Hz, 1H), 1.62 (m,1H), 0.49-0.36 (m, 4H).

Example 247Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2-fluoroethyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 247F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2-fluoroethyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 247F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.50 g, 3.01 mmol) in N,N-dimethylformamide (15 mL) at 0° C.,were added HATU (1.71 g, 4.51 mmol), N,N-diisopropylethylamine (1.66 mL,9.03 mmol) and the mixture was stirred for 5 min.2-fluoro-N-methylethan-1-amine (1a, 0.510 g, 4.51 mmol) was then addedat the same temperature and the reaction was stirred for 24 h at roomtemperature. After completion, the reaction mixture was diluted withcold water. The solid precipitated was filtered and dried to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2-fluoroethyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 247F) as white solid. Yield: 1.15 g, 69%; MS (ESI) m/z557.41[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 8.10 (s, 1H), 7.99 (s, 1H), 7.21(d, J=7.9 Hz, 2H), 7.08-7.01 (m, 4H), 6.98-6.89 (m, 3H), 5.73 (d, J=16.5Hz, 1H), 5.15 (dd, J=5.5, 17.4 Hz, 1H), 4.85-4.65 (m, 2H), 4.52-4.41 (m,2H), 4.25-4.15 (m, 1H), 3.88 (s, 3H), 3.57-3.52 (m, 2H), 3.35 (s, 2H),2.80 (s, 1H).

Example 2484-((4bS,5R,6S,7S,7aR)-6-(((2-fluoroethyl)(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 248F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-fluoroethyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2-fluoroethyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 1.15 g, 2.06 mmol) in dry tetrahydrofuran (20 ml) at 0° C., boranedimethyl sulphide complex (1.56 g, 20.63 mmol) was added drop wise overa period of 5 min. The reaction mass was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mass was quenched with methanol at 0° C. and heated to refluxfor 16 h. After completion, solvent was removed under reduced pressureand the residue was purified over a plug of silica gel eluting thecompound with 5% methanol in dichloromethane. The desired fractions wereconcentrated under reduced pressure to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-fluoroethyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 0.60 g, (crude), MS (ESI) m/z 543.25[M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-6-(((2-fluoroethyl)(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 248F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-fluoroethyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 1.20 g, 2.20 mmol) in N,N-dimethylformamide (24 mL), zinc cyanide(1.56 g, 13.24 mmol) and zinc dust (0.017 g, 0.264 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.032 g, 0.044 mmol) andtris(dibenzylideneacetone)dipalladium (0.060 g, 0.066 mmol) were addedto the reaction, degassed for additional 5 min and mixture was heated at140° C. for 3 h. After completion, the reaction mass was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by Prep-HPLC toaffordrac-4-((4bS,5R,6S,7S,7aR)-6-(((2-fluoroethyl)(methyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.180 g, 18%; MS (ESI) m/z 490.52[M+1]⁺; Theenantiomers were separated by chiral SFC [chiralpak ID (4.6×250) mm,5μ], CO₂/0.1% TEA in EtOH 80/20 V/V. Peak 1 (40 mg), [α]_(D) −17.3° (c0.25, CHCl₃), R_(t)=4.970 min, ee: 99.54% MS (ESI) m/z 490.24 [M+1]⁺. ¹HNMR (400 MHz, DMSO-d₆) 8.04 (s, 1H), 7.97 (s, 1H), 7.48 (d, J=8.44 Hz,2H), 7.37 (d, J=8.40 Hz, 2H), 7.09-6.97 (m, 5H), 5.73 (s, 1H), 5.06 (d,J=4.96 Hz 1H), 4.57 (bs, 1H), 4.50 (bs, 1H), 4.45 (bs, 1H), 3.88 (s,3H), 3.80 (d, J=13.92 Hz, 1H), 3.22-3.19 (m, 1H), 2.85-2.78 (m, 1H),2.67-2.55 (m, 2H), 2.32 (s, 3H), 2.18-2.12 (m, 1H). Peak 2 (Cpd. No.248F, 57 mg), [α]_(D) +18.6° (c 0.276, CHCl₃), R_(t)=5.948 min, ee:95.18% MS (ESI) m/z 490.31 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) 8.04 (s,1H), 7.97 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H),7.09-6.97 (m, 5H), 5.73 (s, 1H), 5.06 (d, J=4.9 Hz 1H), 4.57 (bs, 1H),4.50 (bs, 1H), 4.45 (bs, 1H), 3.88 (s, 3H), 3.80 (d, J=13.9 Hz, 1H),3.22-3.19 (m, 1H), 2.85-2.78 (m, 1H), 2.67-2.55 (m, 2H), 2.32 (s, 3H),2.19-2.16 (m, 1H).

Example 249Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 249F)

Synthesis of tert-butyl ((1-methyl-1H-pyrazol-5-yl) methyl)carbamate (2)

To a solution of (1-methyl-1H-pyrazol-5-yl)methanamine (1, 0.5 g, 4.5mmol) in dichloromethane (10 mL) and triethylamine (0.627 ml, 4.5 mmol)at 0° C., di-tert-butyl dicarbonate (0.982 g, 4.5 mmol) was addeddropwise and reaction mixture stirred at room temperature for 2 h. Thereaction mixture was concentrated and crude obtained was purified bycombi-flash (4 g, RediSep column) using 30% ethyl acetate in hexane as aeluent. The combined pure fractions were concentrated to affordtert-butyl ((1-methyl-1H-pyrazol-5-yl) methyl)carbamate (2) as acolourless liquid. Yield: 0.61 g, 67%; MS (ESI) m/z 212.31[M+1]⁺.

Synthesis of N-methyl-1-(1-methyl-1H-pyrazol-5-yl)methanamine (3)

To a solution of compound tert-butyl(1-methyl-1H-pyrazol-5-yl)methyl)carbamate (2, 0.6 g, 2.84 mmol) intetrahydrofuran at 0° C. was added drop wise lithium aluminum hydride(11.36 ml, 11.36 mmol, 1M in THF) and reaction mixture was heated at 70°C. for 4 h. The reaction mixture was cooled to 0° C. and quenched slowlyby addition of aqueous sodium hydroxide slowly over a period of 15 to 20minutes. The resulting suspension was diluted with Ethyl acetate &passed through celite pad. The filtrate obtained was dried overanhydrous sodium sulphate filtered and concentrated to get pureN-methyl-1-(1-methyl-1H-pyrazol-5-yl)methanamine (3). Yield 0.305 g,85.9%.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 249F)

To the solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (4, 1.00 g, 2.01 mmol) in N,N-dimethylformamide (20 ml) at 0° C.,HATU (2.29 g, 6.03 mmol) and N,N-diisopropylethylamine (1.81 g, 14.0mmol) were added and the mixture was stirred for 5 min.N-methyl-1-(1-methyl-1H-pyrazol-5-yl)methanamine (3, 1.24 g, 10.06 mmol)was then added at the same temperature and then reaction mixture wasstirred for 16 h. at room temperature. After completion, the reactionmixture was diluted with cold water to get solid. Solid obtained wasfiltered, dried and triturated with pentane to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 249F) as a white solid. Yield: 0.90 g, 74%; MS (ESI) m/z605.26[M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) □ 8.11 (s, 1H), 8.00 (s, 1H),7.30 (s, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 7.05-6.93(m, 5H), 6.21 (s, 1H), 5.70 (s, 1H), 5.23 (bs, 1H), 4.78 (t, J=4.8 Hz,1H), 4.60 (d, J=15.2 Hz, 1H), 4.49-4.41 (m, 2H), 4.26-4.21 (m, 1H), 3.88(s, 3H), 3.56 (s, 3H), 3.20 (s, 3H).

Example 2504-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 250F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methyl((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 1.20 g, 1.98 mmol) in dry tetrahydrofuran (20 ml) at 0° C., boranedimethyl sulphide complex (2.7 mL, 29.8 mmol) was added drop wise over aperiod of 5 min. The reaction mixture was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mixture was quenched with methanol (40 ml) at 0° C. and heatedto reflux for 24 h. After completion, solvent was removed under reducedpressure and crude obtained was purified by silica gel (100-200 meshsize) column chromatography using 2% methanol in dichloromethane aseluent. The desired fractions were concentrated under reduced pressureto affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methyl((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) Yield: 0.75 g, 64%; MS (ESI) m/z 589.51[M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 250F)

To a solution ofrac-((4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methyl((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.75 g, 1.27 mmol) in N,N-dimethylformamide (10 mL), zinc cyanide(1.48 g, 12.7 mmol) and zinc dust (0.009 g, 0.131 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15minutes. 1,1′-Bis(diphenylphosphino)ferrocene (0.014 g, 0.025 mmol) andtetrakis(triphenylphosphine) palladium (0.044 g, 0.038 mmol) were addedto the reaction mixture, degassed for additional 5 min and mixture washeated at 140° C. for 8 h. After completion, the reaction mixture wasdiluted with ethyl acetate and washed with cold water. The organic layerwas separated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel (100-200 mesh size) column chromatography using 6% methanolin dichloromethane as eluent. The desired fractions were concentrated toaffordrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.28 g, 41%; The enantiomers were separated bychiral SFC [CHIRALPAK ID (4.6×250)mm, 5μ] in CO2/0.1% TEA inEtOH=(60/40) Peak 1 (Cpd. No. 250F, 83 mg), [α]_(D) −46.0° (c 0.25,CHCl₃), R_(t)=2.15 min, ee 99.76%; MS (ESI) m/z 538.36[M+1]⁺. ¹H NMR(400 MHz, DMSO-d₆) 8.04 (s, 1H), 7.98 (s, 1H), 7.47 (d, J=8.0 Hz, 2H),7.34 (d, J=8.0 Hz, 2H), 7.30 (s, 1H), 7.07-7.03 (m, 2H), 6.99-6.96 (m,3H), 6.11 (s, 1H), 5.75 (s, 1H), 5.10 (d, J=4.4 Hz, 1H), 4.52 (bs, 1H),3.89 (s, 3H), 3.84 (s, 3H), 3.78 (d, J=14.0 Hz, 1H), 3.62 (d, J=13.6 Hz,1H), 3.43 (d, J=13.8 Hz, 1H), 3.17 (bs, 1H), 2.73-2.66 (m, 1H), 2.21 (s,3H), 2.14 (d, J=11.2 Hz, 1H); Peak-2 (94 mg), [α]D+39.0° (c 0.309,CHCl₃), Rt=2.59 min, ee 98.04%; MS (ESI) m/z 538.36 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆) 8.04 (s, 1H), 7.98 (s, 1H), 7.47 (d, J=8.0 Hz, 2H), 7.34(d, J=8.0 Hz, 2H), 7.30 (s, 1H), 7.07-7.03 (m, 2H), 6.99-6.96 (m, 3H),6.11 (s, 1H), 5.75 (s, 1H), 5.10 (d, J=4.40 Hz, 1H), 4.52 (bs, 1H), 3.89(s, 3H), 3.84 (s, 3H), 3.78 (d, J=14.0 Hz, 1H), 3.63 (d, J=13.6 Hz, 1H),3.43 (d, J=13.8 Hz, 1H), 3.18 (bs, 1H), 2.73-2.66 (m, 1H), 2.21 (s, 3H),2.14 (d, J=11.2 Hz, 1H).

Example 251Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxy-2-methylpropyl)-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 251F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxy-2-methylpropyl)-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 251F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.50 g, 3.01 mmol) in N,N-dimethylformamide (15 mL) at 0° C.,1-[Bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (1.71 g,4.51 mmol), N,N-diisopropylethylamine (1.66 mL, 9.03 mmol) were addedand the reaction mixture was stirred for 5 min.2-methyl-1-(methylamino)propan-2-ol (1.550 g, 15.05 mmol) was then addedat the same temperature and the reaction was stirred for 24 h at roomtemperature. After completion, the reaction mixture was diluted withcold water. The solid precipitated was filtered and dried to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxy-2-methylpropyl)-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 251F) as white solid. Yield: 1.315 g, 82%; MS (ESI) m/z583.38[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 8.10 (s, 1H), 7.99 (s, 1H), 7.22(d, J=8.44 Hz, 2H), 7.14-6.91 (m, 7H), 5.09-4.96 (m, 1H), 4.79 (bs, 1H),4.59-4.40 (m, 2H), 4.22 (dd, J=4.84, 13.48 Hz, 1H), 3.88 (bs, 4H), 3.40(s, 3H), 3.12 (d, J=7.4 Hz, 1H), 2.82 (s, 1H), 0.99 (s, 3H), 0.93 (s,3H).

Example 2524-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxy-2-methylpropyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 252F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-hydroxy-2-methylpropyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxy-2-methylpropyl)-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 1.2 g, 2.05 mmol) in dry tetrahydrofuran (20 ml) at 0° C., boranedimethyl sulphide complex (2.34 g, 30.85 mmol) was added drop wise overa period of 5 min. The reaction mixture was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mixture was quenched with methanol at 0° C. and heated toreflux for 16 h. After completion, solvent was removed under reducedpressure and the residue was purified by silica gel (100-200 mesh size)column chromatography using 5% methanol in dichloromethane as eluent.The desired fractions were concentrated under reduced pressure to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-hydroxy-2-methylpropyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 1.0 g, (crude), MS (ESI) m/z 569.46[M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxy-2-methylpropyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 252F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-hydroxy-2-methylpropyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 1.0 g, 1.75 mmol) in N,N-dimethylformamide (10 mL), zinc cyanide(1.23 g, 10.53 mmol) and zinc dust (0.057 g, 0.875 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.097 g, 0.175 mmol) andtris(dibenzylideneacetone)dipalladium (0.080 g, 0.087 mmol) were addedto the reaction mixture, degassed for additional 5 min and reactionmixture was heated at 140° C. for 7 h. After completion, the reactionmixture was diluted with ethyl acetate and washed with cold water. Theorganic layer was separated and dried over anhydrous sodium sulphate,filtered and concentrated to give crude product. The crude product waspurified by Preparative HPLC to affordrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxy-2-methylpropyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.273 g, 30%; MS (ESI) m/z 516.53[M+1]⁺. Theenantiomers were separated by chiral SFC [chiralpak IG (4.6×250) mm,5μ], CO₂/0.1% TEA in MeOH (60/40). Peak 1 (88 mg), [α]_(D) −34.4° (c0.45, CHCl₃), R_(t)=1.929 min, ee: 99.92% MS (ESI) m/z 490.24 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) 8.04 (s, 1H), 7.96 (s, 1H), 7.48 (d, J=8.3 Hz,2H), 7.37 (d, J=8.4 Hz, 2H), 7.08-6.98 (m, 5H), 5.72 (s, 1H), 5.15 (s,1H), 4.61 (d, J=6.4 Hz, 2H), 3.89 (s, 3H), 3.79 (d, J=13.8 Hz, 1H),3.23-3.16 (m, 1H), 2.66-2.60 (m, 1H), 2.43 (s, 3H), 2.29 (bs, 1H), 2.20(s, 2H), 1.13 (s, 3H), 1.02 (s, 3H). Peak 2 (Cpd. No. 252F, 95 mg),[α]_(D) +32.0° (c 0.30, CHCl₃), R_(t)=3.157 min, ee: 98.9% MS (ESI) m/z516.53 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d6) □ 8.04 (s, 1H), 7.96 (s, 1H),7.48 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.09-6.97 (m, 5H), 5.72(s, 1H), 5.15 (s, 1H), 4.61 (bs, 2H), 3.89 (s, 3H), 3.79 (d, J=13.8 Hz,1H), 3.22-3.20 (m, 1H), 2.66-2.60 (m, 1H), 2.43 (s, 3H), 2.29 (bs, 1H),2.20 (s, 2H), 1.13 (s, 3H), 1.02 (s, 3H).

Example 253Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxy-2-methylpropyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 253F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxy-2-methylpropyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 253F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.50 g, 3.01 mmol) in N,N-dimethylformamide (30 mL) at 0° C.,1-[Bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (1.71 g,4.51 mmol), N,N-diisopropylethylamine (1.16 g, 9.03 mmol) were added andthe mixture was stirred for 5 min. 1-amino-2-methylpropan-2-ol (0.804 g,9.03 mmol) was then added at the same temperature and the reaction wasstirred for 24 h at room temperature. After completion, the reactionmass was diluted with cold water. The solid precipitated was filteredand dried to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxy-2-methylpropyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 253F) as white solid. Yield: 0.80 g, 46%; MS (ESI) m/z569.23[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 8.23 (bs, 1H), 8.08 (s, 1H),7.98 (s, 1H), 7.23 (d, J=8.5 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 7.05-6.99(m, 5H), 5.67 (s, 1H), 5.03 (d, J=3.4 Hz, 1H), 4.57 (bs, 1H), 4.43 (s,1H), 4.33 (d, J=14.16 Hz, 1H), 4.10-4.06 (m, 1H), 3.87 (s, 3H), 2.99 (d,J=5.88 Hz, 2H), 0.98 (s, 3H), 0.93 (s, 3H).

Example 2544-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxy-2-methylpropyl)amino)methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 254F)

Synthesis ofrac-((4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-hydroxy-2-methylpropyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxy-2-methylpropyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 0.7 g, 1.22 mmol) in dry tetrahydrofuran (14 ml) at 0° C., boranedimethyl sulphide complex (0.933 g, 12.29 mmol) was added drop wise overa period of 5 min. The reaction mixture was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mixture was quenched with methanol at 0° C. and heated toreflux for 16 h. After completion, solvent was removed under reducedpressure and the residue was purified over a plug of silica gel (100-200mesh size) eluting the compound with 5% methanol in dichloromethane aseluent. The desired fractions were concentrated under reduced pressureto affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-hydroxy-2-methylpropyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 0.559 g, 82%; MS (ESI) m/z 555.47[M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxy-2-methylpropyl)amino)methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 254F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-hydroxy-2-methylpropyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.55 g, 0.99 mmol) in N,N-dimethylformamide (10 mL), zinc cyanide(0.175 g, 1.48 mmol) and zinc dust (0.0064 g, 0.099 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.072 g, 0.099 mmol) andtris(dibenzylideneacetone)dipalladium (0.027 g, 0.029 mmol) were addedto the reaction, degassed for additional 5 min and mixture was heated at140° C. for 3 h. After completion, the reaction mixture was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel (100-200 mesh size) column chromatography using 3-5% methanolin dichloromethane as eluent. The desired fractions were concentrated toaffordrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxy-2-methylpropyl)amino)methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.250 g, 51%; MS (ESI) m/z 502.29[M+1]⁺. Theenantiomers were separated by chiral HPLC [Chiralpak IA (4.6×250) mm,5μ] in 0.1% TEA in n-Hexane/EtOH=85/15 (V/V). Peak 1 (Cpd. No. 254F, 40mg), [α]_(D) +5.20° (c 0.257, CHCl₃), R_(t)=13.139 min, ee: 99.88%; MS(ESI) m/z 502.28[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) 8.04 (s, 1H), 7.96 (s,1H), 7.48 (d, J=8.40 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.07-6.95 (m, 5H),5.68 (s, 1H), 5.48 (bs, 1H), 4.55 (d, J=3.76 Hz, 1H), 4.19 (s, 1H), 3.86(s, 3H), 3.82 (d, J=14.4 Hz, 1H), 3.18 (bs, 1H), 2.74-2.69 (m, 1H), 2.55(bs, 2H), 2.41 (s, 1H), 2.30 (s, 1H), 1.05 (s, 6H). Peak-2 (30 mg),[α]_(D) −9.2° (c 0.23, CHCl₃), R_(t)=27.70 min, ee:99.16%; MS (ESI) m/z502.28[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) 8.04 (s, 1H), 7.96 (s, 1H), 7.48(d, J=8.40 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.07-6.98 (m, 5H), 5.68 (s,1H), 5.48 (bs, 1H), 4.55 (bs, 1H), 4.18 (s, 1H), 3.86 (s, 3H), 3.82 (d,J=14.28 Hz, 1H), 3.17 (bs, 1H), 2.73-2.68 (m, 1H), 2.55 (bs, 2H), 2.43(bs, 1H), 2.30 (s, 1H), 1.05 (s, 6H).

Example 255Rac-(4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(p-tolyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 255F)

Synthesis of(E)-1-(3-hydroxy-5-methoxypyridin-4-yl)-3-(p-tolyl)prop-2-en-1-one (3)

To a solution of 1-(3-hydroxy-5-methoxypyridin-4-yl)ethan-1-one (1, 10.0g, 59.8 mmol) in methanol (250 mL), sodium hydroxide (7.1 g, 179.6 mmol)was added followed by addition of 4-methylbenzaldehyde (2, 7.1 g, 59.8mmol). The reaction was heated to reflux for 1 h. After completion, thereaction mixture was cooled to room temperature, diluted with water (200mL) The solid precipited out was filtered and dried over vacuum to getthe crude product. The crude product was triturated with pentane, anddried under vacuum to afford(E)-1-(3-hydroxy-5-methoxypyridin-4-yl)-3-(p-tolyl)prop-2-en-1-one (3)as yellow solid. Yield: 16.0 g, 99%; MS (ESI) m/z 270.12[M+1]⁺.

Synthesis of3-hydroxy-5-methoxy-2-(p-tolyl)-4H-pyrano[2,3-c]pyridin-4-one (4)

To a solution of(E)-1-(3-hydroxy-5-methoxypyridin-4-yl)-3-(p-tolyl)prop-2-en-1-one (3,16.0 g, 59.4 mmol) in ethanol (480 mL) at 0° C., sodium hydroxide (2.8g, 71.3 mmol) was added followed by the addition of 30% aqueous hydrogenperoxide (47.1 mL, 416.2 mmol). The reaction mass was stirred for 30 minat 60° C. After completion, the reaction mass was cooled and neutralizedto pH ˜7 by the addition of 6 M hydrogen chloride. Then filtered anddried. The solid obtained was triturated with ethanol, filtered anddried under vacuum to afford3-hydroxy-5-methoxy-2-(p-tolyl)-4H-pyrano[2,3-c]pyridin-4-one (4) asyellow solid. Yield: 3.8 g, 23.0%; MS (ESI) m/z 284.32[M+1]⁺.

Synthesis of rac-methyl(3S,4S,5R)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2-(p-tolyl)-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(6)

To a solution of3-hydroxy-5-methoxy-2-(p-tolyl)-4H-pyrano[2,3-c]pyridin-4-one (4, 3.80g, 13.5 mmol) and methyl cinnamate (5, 21.93 g, 135.2 mmol) indichloromethane (300 mL), acetonitrile (150 mL) and methanol (150 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedunder 400 watts UV light for 12 h. After completion, solvent was removedunder reduced pressure and the residue was purified by silica gel(100-200 mesh size) using ethyl acetate as eluent. The desired fractionswere concentrated under reduced pressure to afford rac-methyl(3S,4S,5R)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2-(p-tolyl)-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(6) as yellow brown solid. Yield: 5.0 g, crude. MS (ESI) m/z 446.46[M+1]⁺.

Synthesis of rac-methyl(4bR,6R,7S,7aR)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-7a-(p-tolyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7)

The crude compound rac-methyl(3S,4S,5R)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2-(p-tolyl)-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(6, 5.0 g) was suspended in methanol (50 mL) and treated with 25% sodiummethoxide in methanol (24 mL). The reaction was heated at 80° C. for 3h. After completion, the solvent was removed under reduced pressure. Thecrude residue was diluted with aqueous ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and concentrated under reduced pressure to affordof rac-methyl(4bR,6R,7S,7aR)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-7a-(p-tolyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7) as off white solid. Yield: 4.5 g, crude. MS (ESI) m/z 446.46 [M+1]⁺.

Synthesis of rac-methyl(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(p-tolyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8)

To a solution of rac-methyl(4bR,6R,7S,7aR)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-7a-(p-tolyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7, 4.50 g, 10.11 mmol) in acetonitrile (45 mL) at 0° C. were addedsodium triacetoxyborohydride (21.93 g, 101.1 mmol), and acetic acid (5ml, 101.1 mmol). The resulting mixture was stirred for 4 h at roomtemperature. After completion, the reaction mixture was partitionedbetween saturated aqueous sodium bicarbonate solution and ethyl acetate.The organic layer was separated, dried over sodium sulphate, filteredand concentrated under reduced pressure to get the crude. The crude waspurified by silica gel column chromatography using 0-5% methanol indichloromethane as eluents. The desired fractions were concentratedunder reduced pressure to afford rac-methyl(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(p-tolyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8) as off white solid. Yield: 2.5 g, 55.3%; MS (ESI) m/z 448.43[M+1]⁺.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(p-tolyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (9)

To a solution of rac-methyl(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(p-tolyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8, 2.50 g, 5.59 mmol) in methanol:tetrahydrofuran:water (2:1:1, 50 mL),lithium hydroxide (1.34 g, 55.9 mmol) was added and the reaction wasstirred for 3 h at room temperature. After completion, the reactionmixture was cooled to 0° C. and acidified with 1 M hydrochloric acid topH ˜2-3. The precipitate obtained was filtered and dried under vacuum toaffordrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(p-tolyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (9) as white solid. Yield: 2.0 g, 83%; MS (ESI) m/z 434.26[M+1]⁺.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-7a-(p-tolyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 255F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(p-tolyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (9, 0.5 g, 1.15 mmol) in dichloromethane (15 mL) at 0° C.,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluorophosphate, (1.31 g, 3.77 mmol) and N,N-diisopropylethylamine(1.23 ml, 6.90 mmol) were added and the mixture was stirred for 5 min.Dimethylamine hydrochloride (0.470 g, 5.77 mmol) was added at the sametemperature and the reaction was stirred for 16 h at room temperature.After completion, the reaction mixture was diluted with dichloromethaneand washed with ice cold water. The organic layer was separated anddried over sodium sulphate, filtered and concentrated to give crudeproduct. The crude product was purified by silica gel (100-200 meshsize) column chromatography using 0-5% methanol in dichloromethane aseluent. The desired fractions were concentrated to affordrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-7a-(p-tolyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 255F) as white solid. Yield: 0.5 g, 94%; MS (ESI) m/z461.29[M+1]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.98 (s, 1H),7.02-6.91 (m, 5H), 6.88-6.83 (m, 4H), 5.52 (s, 1H), 5.01 (d, J=5.08 Hz,1H), 4.78 (t, J=5.32 Hz, 1H), 4.33 (d, J=13.44 Hz, 1H), 4.14 (dd, J=5.56Hz, J=13.48 Hz, 1H), 3.87 (s, 3H), 3.26 (s, 3H), 2.76 (s, 3H), 2.11 (s,3H).

Example 256(4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(p-tolyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 256F)

Synthesis of(4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(p-tolyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (Cpd. No.256F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-7a-(p-tolyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 0.6 g, 1.3 mmol) in dry tetrahydrofuran (20 ml) at 0° C., boranedimethyl sulphide complex (1.48 ml, 19.5 mmol) was added drop wise overa period of 5 min. The reaction mixture was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mixture was quenched with methanol at 0° C. and heated toreflux for 10 h. After completion, solvent was removed under reducedpressure and the residue was purified by silica gel (100-200 mesh size)eluting the compound with 0-5% methanol in dichloromethane as eluent.The desired fractions were concentrated under reduced pressure to affordrac-(4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(p-tolyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diolas white solid. Yield: 0.330 g. The enantiomers were separated by chiralSFC [CHIRALPAK IG (4.6×150) mm, 5μ] in CO₂/0.1% TEA in EtOH=(60/40).Peak 1 (Cpd. No. 256F, 86 mg), [α]_(D) −32.0° (c 0.51, CHCl₃),R_(t)=3.302 min, ee: 99.86%; MS (ESI) m/z 447.28[M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.00 (s, 1H), 7.93 (s, 1H), 7.07-7.03 (m, 4H), 6.99-6.93 (m,3H), 6.84 (d, J=7.76 Hz, 2H), 5.46 (s, 1H), 5.01 (s, 1H), 4.49 (s, 1H),3.87 (s, 3H), 3.65 (d, J=13.84 Hz, 1H), 3.17-3.06 (m, 1H), 2.55 (s, 1H),2.18 (s, 6H), 2.10 (s, 3H), 1.92 (d, J=11.92 Hz, 1H); Peak-2 (87 mg),[α]_(D) +35.2° (c 0.269, CHCl₃), R_(t)=4.149 min, ee: 99.90%; MS (ESI)m/z 447.28[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (s, 1H), 7.93 (s,1H), 7.07-7.03 (m, 4H), 6.99-6.93 (m, 3H), 6.84 (d, J=7.76 Hz, 2H), 5.46(s, 1H), 5.01 (s, 1H), 4.49 (s, 1H), 3.87 (s, 3H), 3.65 (d, J=13.84 Hz,1H), 3.17-3.06 (m, 1H), 2.55 (s, 1H), 2.18 (s, 6H), 2.10 (s, 3H), 1.92(d, J=11.92 Hz, 1H).

Example 257Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(piperidin-1-yl)methanone(Cpd. No. 257F)

Synthesis ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(piperidin-1-yl)methanone(Cpd. No. 257F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.0 g, 2.0 mmol) in dichloromethane (25.0 mL),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (1.16 g, 6.0 mmol),hydroxybenzotriazole (0.82 g, 6.0 mmol) and N,N-diisopropylethylamine(1.5 mL, 12.2 mmol) were added at 0° C. and stirred the mixture for 5min. piperidine (2, 0.297 g, 10.1 mmol) was then added at sametemperature and the reaction was stirred at room temperature for 5 h.After completion, reaction mass was diluted with dichloromethane (20 mL)and washed with cold water. The organic layer was separated and driedover anhydrous sodium sulphate, filtered and concentrated under reducedpressure. The crude was purified by reverse phase HPLC to affordrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(piperidin-1-yl)methanone(Cpd. No. 257F) as white solid. Yield: 0.80 g, 70%; MS (ESI) m/z565.26[M+1]⁺, UPLC: 99.79%; ¹H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H),7.98 (s, 1H), 7.20 (d, J=8.0 Hz, 2H), 7.07-7.02 (m, 4H), 6.97-6.93 (m,1H), 6.90 (d, J=8.1 Hz, 2H), 5.71 (s, 1H), 5.11 (d, J=5.4 Hz, 1H), 4.67(t, J=5.1 Hz, 1H), 4.47 (d, J=13.3 Hz, 1H), 4.18 (dd, J=4.9 Hz, 13.2 Hz,1H), 3.87 (s, 3H), 3.73 (bs, 2H), 3.35 (m, 2H), 1.75-1.64 (m, 4H),1.46-1.34 (m, 2H).

Example 2584-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(piperidin-1-ylmethyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 258F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(piperidin-1-ylmethyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (2)

To a solution ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(piperidin-1-yl)methanone(1, 0.80 g, 1.6 mmol) in tetrahydrofuran, borane dimethylsulfide (1.2ml, 16.0 mmol) was added at 0° C. The reaction mixture was stirred for 3h at room temperature. After completion, reaction mass was quenched withmethanol at 0° C. and then heated at 60° C. for 4 h. The solvents wereconcentrated give crude. The crude was purified by Combi-flash (4 g,RediSep column) using 7% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(piperidin-1-ylmethyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 0.4 g, 60%; MS (ESI) m/z 551.1[M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(piperidin-1-ylmethyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 258F)

To a mixture ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(piperidin-1-ylmethyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.4 g, 0.72 mmol) in N,N-dimethylformamide (3.0 mL) at roomtemperature, zinc cyanide (0.508 g, 4.34 mmol) and zinc (0.047 g, 0.72mmol) were added at room temperature and degassed the mixture with argonfor 15 min. 1,1′-Bis(diphenylphosphino) ferrocene (0.092 g, 0.166 mmol)and tris(dibenzylideneacetone)dipalladium (0.152 g, 0.166 mmol) wereadded to the reaction mixture and degassing was continued for another 5min. The reaction mixture was heated at 140° C. for 2.5 h. Aftercompletion, the reaction was cooled to room temperature and passedthrough celite bed. The filtrate was diluted with ethyl acetate andwashed with water. The organic layer was separated, dried over anhydroussodium sulphate and concentrated under reduced pressure to give thecrude. The crude was purified by combi-flash (12 g, RediSep column)using 0-10% methanol in dichloromethane as eluent. The product obtainedwas repurified by reverse phase prep HPLC. The desired fractions werelyophilized to affordrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(piperidin-1-ylmethyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.350 g, 82%. The enantiomers were separated bychiral preparative HPLC [Chiralpak IA (4.6×250) mm] using 0.1% TEA inn-Hexane/IPA(80/20) (v/v) mobile phase. Peak 1 (31 mg); [α]_(D) +11.5°(c 0.34, CHCl₃), R_(t)=14.5, ee>99%; MS (ESI) m/z 498.32 [M+1]⁺; UPLC:97.70%. ¹H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.96 (s, 1H), 7.51 (d,J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 7.12-7.07 (m, 2H), 7.05-6.99 (m,3H), 5.72 (s, 1H), 4.50 (d, J=3.6 Hz, 1H), 3.87 (s, 3H), 3.81 (d, J=13.8Hz, 1H), 2.32-2.27 (m, 3H), 2.09 (d, J=11.6 Hz, 1H), 1.64 (s, 2H),1.52-1.50 (m, 5H), 1.37 (s, 3H). Peak-2 (Cpd. No. 258F, 17 mg); [α]_(D)−10.4° (c 0.23, CHCl₃), R_(t)=22.8, ee>99%; MS (ESI) m/z 497.91 [M+1]⁺;UPLC: 99.60%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.96 (s, 1H),7.48 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 7.08-7.05 (m, 2H),7.01-6.96 (m, 3H), 5.72 (s, 1H), 5.38 (bs, 1H), 4.50 (d, J=3.4 Hz, 1H),3.87 (s, 3H), 3.80 (d, J=14.0 Hz, 1H), 2.28-2.24 (m, 2H), 2.06 (d,J=11.2 Hz, 1H), 1.88 (s, 4H), 1.59-1.51 (m, 4H), 1.40-1.37 (m, 2H).

Example 259Rac-4-((4bS,5R,6S,7S,7aR)-6-(((2-fluoroethyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 259F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2-fluoroethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 0.350 g, 0.702 mmol) in N,N-dimethylformamide (3.5 mL) at 0°C.,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (0.40 g, 1.05 mmol), and N,N-diisopropylethylamine(0.34 mL, 2.10 mmol) were added at 0° C. The reaction mixture wasstirred for 5 min at and 2-fluoroethan-1-amine hydrochloride (0.349 g,3.51 mmol) was then added at the same temperature and the reaction wasstirred for 24 h at room temperature. After completion, the reactionmixture was diluted with cold water. The solid precipitated was filteredand dried to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2-fluoroethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(2) as white solid. Yield: 0.34 g, 89%; MS (ESI) m/z 543.39[M+1]⁺.

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-fluoroethyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2-fluoroethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(2, 0.34 g, 0.626 mmol) in dry tetrahydrofuran (10 ml) at 0° C., boranedimethyl sulphide complex (0.951 g, 12.52 mmol) was added drop wise overa period of 5 min. The reaction mixture was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mixture was quenched with methanol at 0° C. and heated toreflux for 16 h. After completion, solvent was removed under reducedpressure and the crude product was by silica gel (100-200 mesh size)column chromatography using 5% methanol in dichloromethane as eluent.The desired fractions were concentrated under reduced pressure to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-fluoroethyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3) as white solid. Yield: 0.250 g, 76%; MS (ESI) m/z 529.42[M+1]⁺.

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-6-(((2-fluoroethyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 259F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(((2-fluoroethyl)amino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3, 0.25 g, 0.472 mmol) in N,N-dimethylformamide (6 mL), zinc cyanide(0.083 g, 0.708 mmol) and zinc dust (0.003 g, 0.047 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.034 g, 0.047 mmol) andtris(dibenzylideneacetone)dipalladium (0.012 g, 0.014 mmol) were addedto the reaction, degassed for additional 5 min and mixture was heated at140° C. for 3 h. After completion, the reaction mixture was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude product was purified by reversephase Preparative HPLC to affordrac-4-((4bS,5R,6S,7S,7aR)-6-(((2-fluoroethyl)amino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 259F) as white solid. Yield: 0.015 g, 7%; MS (ESI) m/z476.25[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) □ 8.13 (s, 1H), 8.06 (s, 1H),7.58 (d, J=8.32 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H), 7.12-7.01 (m, 5H), 5.92(s, 1H), 5.27 (d, J=4.8 Hz, 1H), 4.77 (s, 1H), 4.71 (s, 1H), 4.65 (s,1H), 3.91 (s, 3H), 3.84 (d, J=14.2 Hz, 1H), 3.42-3.30 (m, 4H), 3.15-3.10(t, J=9.0 Hz, 1H), 2.85 (d, J=7.6 Hz, 1H).

Example 260Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(2-methoxyethyl)-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 260F)

Synthesis ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(2-methoxyethyl)-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 260F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid(1, 1.50 g, 3.01 mmol) in N,N-dimethylformamide (15 mL) at 0° C.,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (1.71 g, 4.51 mmol), N,N-diisopropylethylamine (1.66mL, 9.03 mmol) were added and the mixture was stirred for 5 min.2-methoxy-N-methylethan-1-amine (1.340 g, 15.05 mmol) was then added atthe same temperature and the reaction was stirred for 24 h at roomtemperature. After completion, the reaction mixture was diluted withcold water. The solid precipitated was filtered and dried to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(2-methoxyethyl)-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 260F) as white solid. Yield: 1.315 g, 82%; MS (ESI) m/z569.38[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) 8.10 (d, J=3.56 Hz, 1H), 7.99(d, J=3.76 Hz, 1H), 7.24 (d, J=17.24 Hz, 2H), 7.07-6.89 (m, 7H), 5.72(s, 1H), 5.70 (d, J=7.24 Hz, 1H), 5.09 (dd, J=5.32, 13.08 Hz, 1H),4.74-4.69 (m, 1H), 4.46-4.35 (m, 1H), 4.19-4.13 (m, 1H), 3.88 (d, J=3.56Hz, 3H), 3.71-3.60 (m, 2H), 3.66 (t, J=10.36 Hz, 1H), 3.44 (s, 2H), 3.20(s, 1H), 2.78 (s, 3H).

Example 2614-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(((2-methoxyethyl)(methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 261F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(((2-methoxyethyl)(methyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(2-methoxyethyl)-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 1.100 g, 1.93 mmol) in dry tetrahydrofuran (20 ml) at 0° C., boranedimethyl sulphide complex (2.19 g, 28.95 mmol) was added drop wise overa period of 5 min. The reaction mass was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mass was quenched with methanol at 0° C. and heated to refluxfor 16 h. After completion, solvent was removed under reduced pressureand the residue was purified over a plug of silica gel eluting thecompound with 5% methanol in dichloromethane. The desired fractions wereconcentrated under reduced pressure to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(((2-methoxyethyl)(methyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 0.39 g, 69%; MS (ESI) m/z 555.46[M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(((2-methoxyethyl)(methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 261F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(((2-methoxyethyl)(methyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.39 g, 0.70 mmol) in N,N-dimethylformamide (4 mL), zinc cyanide(0.494 g, 4.21 mmol) and zinc dust (0.022 g, 0.35 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.038 g, 0.07 mmol) andtris(dibenzylideneacetone)dipalladium (0.032 g, 0.035 mmol) were addedto the reaction, degassed for additional 5 min and mixture was heated at140° C. for 9 h. After completion, the reaction mass was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by Preparative HPLCto affordrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(((2-methoxyethyl)(methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.137 g, 39%; MS (ESI) m/z 502.26[M+1]⁺. Theenantiomers were separated by chiral SFC [chiralpak IC (4.6×250) mm, 5],CO₂/0.1% TEA in ethanol 80/20 (v/v). Peak 1 (44 mg), [α]_(D) −44.1° (c0.27, CHCl₃), R_(t)=6.220 min, ee: 99.64% MS (ESI) m/z 502.26 [M+1]⁺. ¹HNMR (400 MHz, DMSO-d₆) 8.04 (s, 1H), 7.97 (s, 1H), 7.49 (d, J=8.28 Hz,2H), 7.37 (d, J=8.40 Hz, 2H), 7.07-7.00 (m, 5H), 5.72 (s, 1H), 5.0 (bs,1H), 4.50 (bs, 1H), 3.88 (s, 3H), 3.80 (d, J=13.8 Hz, 1H), 3.40 (s, 2H),3.22 (s, 4H), 2.64-2.57 (m, 2H), 2.41-2.39 (m, 1H), 2.29 (s, 3H), 2.17(d, J=10.72 Hz, 1H). Peak 2 (Cpd. No. 261F, 44 mg), [α]_(D) +31.4° (c0.265, CHCl₃), R_(t)=7.523 min, ee: 97.28% MS (ESI) m/z 502.29 [M+1]⁺.¹H NMR (400 MHz, DMSO-d₆) 8.04 (s, 1H), 7.97 (s, 1H), 7.50 (d, J=8.28Hz, 2H), 7.38 (d, J=8.40 Hz, 2H), 7.09-7.00 (m, 5H), 5.72 (s, 1H), 5.0(bs, 1H), 4.50 (bs, 1H), 3.88 (s, 3H), 3.81 (d, J=13.8 Hz, 1H), 3.40 (s,2H), 3.22 (s, 4H), 2.64-2.57 (m, 2H), 2.41-2.39 (m, 1H), 2.29 (s, 3H),2.17 (d, J=10.72 Hz, 1H).

Example 262Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(2-methoxyethyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 262F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(2-methoxyethyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 262F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 2.0 g, 4.01 mmol) in N,N-dimethylformamide (20 mL) at 0° C.,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidhexafluorophosphate(2.28 g, 6.02 mmol), N,N-diisopropylethylamine (1.98 mL, 12.03 mmol)were added and the mixture was stirred for 5 min. 2-methoxyethan-1-amine(1.50 g, 20.05 mmol) was then added at the same temperature and thereaction was stirred for 24 h at room temperature. After completion, thereaction mixture was diluted with cold water. The solid precipitated wasfiltered and dried to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(2-methoxyethyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 262F) as white solid. Yield: 1.55 g, 70%; MS (ESI) m/z555.21[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 8.38 (t, J=5.12 Hz, 1H), 8.08(s, 1H), 7.98 (s, 1H), 7.24 (d, J=8.52 Hz, 2H), 7.08-6.96 (m, 7H), 5.66(s, 1H), 5.03 (d, J=3.88 Hz, 1H), 4.55 (t, J=4.08 Hz, 1H), 4.34 (d,J=14.24 Hz, 1H), 3.95 (dd, J=14.4, 4.4 Hz, 1H), 3.87 (s, 3H), 3.29-3.15(m, 7H).

Example 2634-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(((2-methoxyethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrilehydrochloride (Cpd. No. 263F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(((2-methoxyethyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(2-methoxyethyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 1.50 g, 2.70 mmol) in dry tetrahydrofuran (20 ml) at 0° C., boranedimethyl sulphide complex (3.07 g, 40.5 mmol) was added drop wise over aperiod of 5 min. The reaction mixture was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mixture was quenched with methanol at 0° C. and heated toreflux for 16 h. After completion, solvent was removed under reducedpressure and the residue was purified by silica gel (100-200 mesh size)using 0-10% methanolic ammonia in dichloromethane as eluent. The desiredfractions were concentrated under reduced pressure to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(((2-methoxyethyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 1.00 g, 69%, MS (ESI) m/z 541.21[M+1]⁺.

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(((2-methoxyethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(3)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(((2-methoxyethyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.950 g, 1.75 mmol) in N,N-dimethylformamide (10 mL), zinc cyanide(1.23 g, 10.52 mmol) and zinc dust (0.057 g, 0.875 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.097 g, 0.175 mmol) andtris(dibenzylideneacetone)dipalladium (0.080 g, 0.0875 mmol) were addedto the reaction, degassed for additional 5 min and mixture was heated at140° C. for 16 h. After completion, the reaction mixture was dilutedwith ethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified byPreparative HPLC to affordrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(((2-methoxyethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(3) as white solid. Yield: 0.163 g, 19%; MS (ESI) m/z 488.32[M+1]⁺.

Synthesis oftert-butyl-(((4bS,5R,6S,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methyl)(2-methoxyethyl)carbamate(4)

To a solution ofrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(((2-methoxyethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(3, 0.15 g, 0.37 mmol) in dichloromethane (3 mL) at 0° C., triethylamine(0.08 mL, 0.61 mmol), Boc anhydride (0.1 mL, 0.45 mmol) were added atsame temperature and the mixture was stirred for 1 h at roomtemperature. After completion, the reaction mixture was diluted withcold water, extracted with dichloromethane. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was washed withn-pentane to afford rac-tert-butyl(((4bS,5R,6S,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methyl)(2-methoxyethyl)carbamateas white solid. Yield: 0.15 g, 83%; MS (ESI) m/z 588.56 [M+1]⁺. Theenantiomers were separated by chiral HPLC [chiralpak IC (4.6×250) mm,5μ], n-Hexane/Isopropanol=70/30 (v/v). Peak 1 (48 mg) and Peak 2 (4, 45mg).

Synthesis of4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(((2-methoxyethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrilehydrochloride (Cpd. No. 263F)

To a solution of tert-butyl(((4bR,5S,6R,7R,7aS)-7a-(4-cyanophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methyl)(2-methoxyethyl)carbamate(4, 0.045 g, 0.076 mmol) in dichloromethane (2 mL) at 0° C., 4Mhydrochloric acid in 1,4-Dioxane (1 mL), was added at same temperatureand the mixture was stirred for 3 h at room temperature. Aftercompletion, the reaction mixture was concentrated to give residue. Theresidue obtained was triturated with mixture of ether and n-pentanefiltered and dried to afford4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(((2-methoxyethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrilehydrochloride (Cpd. No. 263F) as white solid. Yield: 0.032 g, 84%; Peak1 (32 mg), [α]_(D) −12.0° (c 0.20, CHCl₃), R_(t)=9.10 min [CHIRALPAK IG(4.6×250)mm, 5μ]CO₂/0.2% Triethylamine in methanol=(80/20)], ee: 99.56%MS (ESI) m/z 488.26 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 8.24 (s, 1H), 8.13(s, 1H), 7.57 (d, J=8.44 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.13-7.04 (m,5H), 6.02 (bs, 1H), 5.44 (bs, 1H), 4.74 (s, 1H), 3.94 (s, 3H), 3.81 (d,J=14.08 Hz, 1H), 3.61 (bs, 3H), 3.31 (s, 3H), 3.15-3.05 (m, 4H), 2.77(bs, 1H).

Example 264Rac-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(Cpd. No. 264F)

Synthesis ofrac-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(Cpd. No. 264F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.5 g, 3.02 mmol) in dichloromethane (20 mL) at 0° C., wereadded1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluorophosphate (1.71 g, 4.52 mmol) and N,N-diisopropylethylamine(3.28 ml, 18.4 mmol). The resulting reaction mixture was stirred for 5min. (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.9 g, 6.03mmol) was then added at the same temperature and the reaction mixturewas stirred for 16 h at room temperature. After completion, the reactionmixture was diluted with dichloromethane and washed with cold water. Theorganic layer was separated, dried over anhydrous sodium sulphate,filtered and concentrated to give crude product. The crude product waspurified by silica gel (100-200 mesh size) column chromatography using0-5% methanol in dichloromethane as eluent. The desired fractions wereconcentrated to affordrac-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(Cpd. No. 264F) as white solid. Yield: 1.70 g, 95%; MS (ESI) m/z593.21[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 1H), 7.99 (s, 1H),7.19 (d, J=8.0 Hz, 2H), 7.08-6.97 (m, 6H), 6.88 (d, J=7.2 Hz, 1H), 5.73(d, J=6.8 Hz, 1H), 5.20 (m, 1H), 4.71-4.63 (m, 2H), 4.52-4.46 (m, 1H),4.31 (bs, 1H), 4.10-4.05 (m, 1H), 3.88 (s, 3H), 3.79-3.70 (m, 2H), 3.52(bs, 2H), 2.08 (bs, 2H), 1.78-1.63 (m, 2H).

Example 2654-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 265F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (2)

To a solution ofrac-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(1, 1.20 g, 2.02 mmol) in dry tetrahydrofuran (20 ml) at 0° C., boranedimethyl sulfide complex (1.90 ml, 20.2 mmol) was added drop wise over aperiod of 5 min. The reaction mass was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mixture was quenched with methanol at 0° C. and heated toreflux for 10 h. After completion, solvent was removed under reducedpressure and the residue was purified by silica gel (100-200 mesh size)column chromatography using 0-5% methanol in dichloromethane as eluent.The desired fractions were concentrated under reduced pressure to affordrac-(4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 1.0 g, (crude); MS (ESI) 579.21 m/z [M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 265F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 1.0 g, 0.17 mmol) in N,N-dimethylformamide (10 mL), zinc cyanide(0.98 g, 0.86 mmol) and zinc dust (0.013 g, 0.020 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.019 g, 0.035 mmol) andtris(dibenzylideneacetone)dipalladium (0.047 g, 0.052 mmol) were addedto the reaction, degassed for additional 5 min and mixture was heated at130° C. for 2 h. After completion, the reaction mixture was diluted withethyl acetate and washed with cold water. The organic layer wasseparated, dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel (100-200 mesh size) column chromatography using 2-3% methanolin dichloromethane as eluent. The desired fractions were concentrated toaffordrac-4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.30 g; MS (ESI) m/z 526.36[M+1]⁺. Theenantiomers were separated by chiral SFC [CHIRALPAK IA (4.6×250) mm, 5μ]in CO₂/0.1% TEA in MeOH (80/20). Peak 1 (Cpd. No. 265F, 72 mg), [α]_(D)−26.5° (c 0.25, CHCl₃), R_(t)=6.077 min, ee: 99.84%; MS (ESI) m/z526.26[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 8.05 (s, 1H), 7.97 (s, 1H), 7.48(d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.09-6.96 (m, 5H), 5.71 (s,1H), 5.38 (s, 1H), 4.61 (s, 1H), 3.88 (s, 3H), 3.82 (d, J=14.2 Hz, 1H),3.56 (d, J=7.6 Hz, 2H), 3.50 (t, J=12.0 Hz, 1H), 3.38 (s, 1H), 3.15 (bs,1H), 2.94 (s, 1H), 2.44-2.41 (m, 2H), 2.23 (d, J=11.2 Hz, 1H), 1.69-1.62(m, 4H). Peak-2 (104 mg), [α]D +39.2° (c 0.258, CHCl₃), R_(t)=7.813 min,ee: 99.68%; MS (ESI) m/z 526.26[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) □ 8.05(s, 1H), 7.97 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H),7.11-6.96 (m, 5H), 5.71 (s, 1H), 5.38 (bs, 1H), 4.61 (s, 1H), 3.88 (s,3H), 3.84 (d, J=13.6 Hz, 1H), 3.56 (d, J=7.6 Hz, 2H), 3.50 (t, J=12.0Hz, 1H), 3.37 (s, 1H), 3.17 (bs, 1H),3.02 (s, 1H), 2.44-2.41 (m, 2H),2.23 (d, J=11.2 Hz, 1H), 1.69-1.62 (m, 4H).

Example 266Rac-((1R,5S)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(Cpd. No. 266F)

Synthesis ofrac-((1R,5S)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(Cpd. No. 266F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.0 g, 2.0 mmol) in dichloromethane (15 mL),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluorophosphate (1.14 g, 6.0 mmol) and N,N-diisopropylethylamine(1.37 ml, 8.0 mmol) were added at 0° C. and stirred the reaction mixturefor 5 min. (1R,5S)-3-oxa-6-azabicyclo[3.1.1]heptane (0.39 g, 4.0 mmol)was then added and the reaction mixture was stirred for 2 h at roomtemperature. After completion, reaction mixture was concentrated and thesolid obtained was taken in ice cold water, filtered and dried to affordrac-((1R,5S)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(Cpd. No. 266F) as off white solid. Yield: 0.92 g, 79%; MS (ESI) m/z579.25[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (s, 1H), 7.98 (s, 1H),7.19 (d, J=8.7 Hz, 2H), 7.10-6.93 (m, 7H), 5.74-4.73 (m, 3H), 4.65-4.16(m, 4H), 4.01-3.73 (m, 7H), 2.57 (bs, 1H), 1.93-1.82 (m, 1H).

Example 267Rac-4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-6-azabicyclo[3.1.]heptan-6-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 267F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-((1R,5S)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(1, 0.35 g, 1.0 mmol) in tetrahydrofuran (15 mL), borane dimethylsulfide (0.57 ml, 6.0 mmol) was added at 0° C. The reaction mixture wasstirred for 6 h at room temperature. After completion, reaction mixturewas quenched with methanol at 0° C. and then heated at 60° C. for 16 h.The reaction mixture was loaded directly onto two 2 g Strata X-C ionexchange columns from Phenomenex. The columns were washed withacetonitrile and then methanol. Then the product was eluted with a 1:2:7mixture of ammonium hydroxide: dichloromethane: methanol. The eluentcontaining the desired product was concentrated to affordrac-(4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 0.11 g, 32%; MS (ESI) m/z 565.25[M+1]⁺.

Synthesis ofrac-4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 267F)

To a mixture ofrac-(4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.15 g, 2.6 mmol) in N,N-dimethylformamide (3.0 mL) at roomtemperature, zinc cyanide (186 mg, 1.59 mmol) and zinc (16 mg, 0.26mmol) were added at room temperature and degassed the mixture with argonfor 15 min. 1,1′-Bis(diphenylphosphino) ferrocene (43 mg, 0.059 mmol)and tris(dibenzylideneacetone)dipalladium (53 mg, 0.059 mmol) were addedto the reaction mixture and degassing was continued for another 5 min.The reaction mixture was heated at 130° C. for 1.5 h. After completion,the reaction was cooled to room temperature and passed through celitebed. The filtrate was diluted with ethyl acetate and washed with water.The organic layer was separated, dried over anhydrous sodium sulphateand concentrated under reduced pressure to give the crude product. Thecrude product was purified by combi-flash (12 g, RediSep column) using0-10% methanol in dichloromethane as eluent. The product obtained wasrepurified by reverse phase preparative HPLC. The desired fractions werelyophilized to affordrac-4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 267F) as white solid. Yield: 0.075 g, 55%; MS (ESI) m/z512.30[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.96 (s, 1H),7.48 (d, J=8.44 Hz, 2H), 7.38 (d, J=8.52 Hz, 2H), 7.10-7.07 (m, 2H),7.03-7.01 (m, 3H), 6.18 (bs, 1H), 5.71 (s, 1H), 4.53 (d, J=3.84 Hz, 1H),3.98 (d, J=10.84 Hz, 1H), 3.87 (bs, 4H), 3.60 (d, J=10.16 Hz, 1H),3.55-3.45 (m, 2H), 3.09-3.06 (m, 1H), 2.81 (dd, J=7.9 Hz, 12.8 Hz, 1H),2.66 (d, J=10.64 Hz, 1H), 2.50-2.43 (m, 2H), 1.88 (s, 1H) 1.62 (d,J=7.88 Hz, 1H).

Example 2684-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 268F)

Synthesis ofrac-((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 0.05 g, 0.10 mmol) in dichloromethane (5.0 mL),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.043 g, 0.32 mmol),hydroxybenzotriazole (0.04 g, 0.3 mmol) and N,N-diisopropylethylamine(0.09 mL, 0.5 mmol) were added at 0° C. and stirred the mixture for 5min. (1R,5S)-8-azabicyclo[3.2.1]octane (2, 0.016 g, 0.15 mmol) was thenadded at same temperature and the reaction was stirred at roomtemperature for 5 h. After completion, reaction mass was diluted withdichloromethane (20 mL) and washed with cold water. The organic layerwas separated and dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure. The crude was purified by reversephase HPLC to affordrac-((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(3) as white solid. Yield: 23.0 mg, 43%. MS (ESI) m/z 591.18[M+1]⁺; UPLC99.6%; ¹H NMR (400 MHz, DMSO-d₆, at High temperature VT(373K) δ: 8.11(s, 1H), 8.01 (s, 1H), 7.21 (d, J=8.6 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H),7.05-6.94 (m, 5H), 4.70 (d, J=4.8 Hz, 1H), 4.52 (d, J=13.2 Hz, 1H),4.09-4.05 (m, 1H), 3.92 (s, 3H), 2.01-1.78 (m, 8H), 1.60-1.55 (m, 4H).

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-6-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (4)

To a solution ofrac-((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(3, 0.50 g, 0.84 mmol) in tetrahydrofuran (10 mL), Borane dimethylsulphide (0.2 mL, 2.1 mmol), was added at 0° C. and stirred the mixturefor 3 h at room temperature. After completion, reaction mass wasquenched with methanol (5.0 mL) and again heated for 10 h at 60° C. Thereaction mixture was concentrated to give crude. The crude was purifiedby combi-flash (12 g, RediSep column) using 5-20% methanol indichloromethane as eluent. The desired fractions were concentrated toaffordrac-(4bS,5R,6S,7S,7aR)-6-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4) as off white solid. Yield: 0.45 g, 92%; MS (ESI) m/z 577.4[M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 268F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-6-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(4, 0.450 g, 0.78 mmol) in N,N-dimethylformamide (5.0 mL), zinc cyanide(0.543 g, 4.6 mmol) and zinc (0.005 g, 0.078 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.130 g, 0.23 mmol),tris(dibenzylideneacetone)dipalladium (0.214 g, 0.023 mmol) were addedto the reaction and degassing was continued for another 5 min. Thereaction mixture was heated at 140° C. for 3 h. After completion, thereaction was cooled to room temperature and passed through celite bed.The filtrate was diluted with ethyl acetate and washed with water. Theorganic layer was separated, dried over anhydrous sodium sulphate andconcentrated under reduced pressure to give the crude. The crude waspurified by combi-flash (4 g, RediSep column) using 0-15% methanol indichloromethane as eluent. The desired fractions were concentrated underreduced pressure. The crude was purified by reverse phase preparativeHPLC and desired fractions were lyophilized to giverac-4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 140 mg, 35%. The enantiomers were separated bychiral preparative HPLC [Chiralpak IA (4.6×250) mm, 5μ]; 0.1% TEA inn-Hexane/IPA=60/40 (V/V); Peak 1 (9 mg), [α]_(D) +33.1° (c 0.27, CHCl₃),R_(t)=9.36, ee>99%; MS (ESI) m/z 523.93[M+1]⁺; UPLC: 98.8%; ¹H NMR (400MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.97 (s, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.37(d, J=8.4 Hz, 2H), 7.09-6.97 (m, 5H), 5.68 (s, 1H), 4.6 (d, J=3.5 Hz,1H), 3.95 (d, J=13.9 Hz, 1H), 3.88 (s, 3H), 3.13-3.11 (m, 1H), 2.97 (bs,1H), 1.90 (s, 2H), 1.76 (m, 1H), 1.74-1.31 (m, 10H); Peak 2 (Cpd. No.268F, 8 mg), [α]_(D) −58.9° (c 0.25, CHCl₃), R_(t)=14.22, ee>99%; MS(ESI) m/z 524.31[M+1]⁺; UPLC: 97.3%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.06(s, 1H), 7.97 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H),7.07-6.98 (m, 5H), 6.05 (s, 1H), 5.69 (s, 1H), 4.6 (s, 1H), 3.95 (m,1H), 3.88 (s, 3H), 3.12 (bs, 1H), 2.95 (bs, 1H), 2.60 (bs, 2H),1.76 (m,1H), 1.59-1.14 (m, 10H).

Example 269Rac-(3aR,4R,4aR,9bS,9cR)-4a-(4-(difluoromethyl)phenyl)-9b-hydroxy-9-methoxy-4-phenyl-3,3a,4,4a,9b,9c-hexahydro-2H-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-2-one(Cpd. No. 269F)

Synthesis ofrac-(3aR,4R,4aR,9bS,9cR)-4a-(4-(difluoromethyl)phenyl)-9b-hydroxy-9-methoxy-4-phenyl-3,3a,4, 4a,9b,9c-hexahydro-2H-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-2-one(Cpd. No. 269F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-(difluoromethyl)phenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 0.5 g, 1.0 mmol) in toluene (10 mL), triethylamine (0.2 mL, 1.5mmol) and diphenylphosphoryl azide (0.29 ml, 1.3 mmol) were added. Thereaction mixture was stirred for 16 h at 80° C. After completion,reaction mass was diluted with water (10 mL) and solid precipitated wasfiltered and washed with pentane then dried to giverac-(3aR,4R,4aR,9bS,9cR)-4a-(4-(difluoromethyl)phenyl)-9b-hydroxy-9-methoxy-4-phenyl-3,3a,4,4a,9b,9c-hexahydro-2H-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-2-one(Cpd. No. 269F) as off white solid. Yield: 0.36 g, 73%; MS (ESI) m/z467.24[M+1]⁺, UPLC: 95.03%; ¹H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H),8.21 (s, 1H), 8.15 (s, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.0 Hz,2H), 7.10-6.79 (m, 6H), 6.03 (s, 1H), 5.43 (d, J=8.3 Hz, 1H), 4.97 (t,J=9.5 Hz, 1H), 3.97 (s, 3H), 3.46 (d, J=10.8 Hz, 1H).

Example 270Rac-(4bS,5R,6R,7R,7aR)-6-amino-7a-(4-(difluoromethyl)phenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 270F)

Synthesis ofrac-(4bS,5R,6R,7R,7aR)-6-amino-7a-(4-(difluoromethyl)phenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 270F)

To a solution ofrac-(3aR,4R,4aR,9bS,9cR)-4a-(4-(difluoromethyl)phenyl)-9b-hydroxy-9-methoxy-4-phenyl-3,3a,4,4a,9b,9c-hexahydro-2H-oxazolo[4″,5″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-2-one(1, 0.35 g, 0.74 mmol) in methanol: water (1:1), sodium hydroxide (0.089g, 2.2 mmol) was added. The reaction mixture was stirred for 16 h at 90°C. After completion, methanol was concentrated and the solid obtainedwas filtered and washed with diethyl ether, dried under vacuum to affordrac-(4bS,5R,6R,7R,7aR)-6-amino-7a-(4-(difluoromethyl)phenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 270F) as white solid. Yield: 0.19 g, 58%; MS (ESI) m/z 441.19[M+1]⁺, UPLC: 97.71%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.91 (s,1H), 7.35-6.68 (m, 10H), 5.54 (bs, 1H), 5.16 (bs, 1H), 4.21 (m, 2H),3.88 (s, 3H), 3.70 (d, J=9.8 Hz, 1H), 1.53 (brs, 2H).

Example 271Rac-((4bS,5R,6R,7S,7aR)-7a-(4-chlorophenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 271F)

Synthesis of(E)-3-(4-chlorophenyl)-1-(3-hydroxy-5-methoxypyridin-4-yl)prop-2-en-1-one(3)

To a solution of 1-(3-hydroxy-5-methoxypyridin-4-yl)ethan-1-one (1, 5.0g, 29.9 mmol) and 4-chlorobenzaldehyde (2, 4.2 g, 29.9 mmol) in methanol(50 mL), sodium hydroxide (3.60 g, 89.8 mmol) was added and the mixturewas heated to reflux for 30 min. After completion, the reaction mixturewas cooled to room temperature, The precipitated solid was filtered,washed with water, n-pentane and dried under high vacuum to afford(E)-3-(4-chlorophenyl)-1-(3-hydroxy-5-methoxypyridin-4-yl)prop-2-en-1-one(3) as yellow solid. Yield: 8.0 g, 92.0%; MS (ESI) m/z 290.39[M+1]⁺.

Synthesis of2-(4-chlorophenyl)-3-hydroxy-5-methoxy-4H-pyrano[2,3-c]pyridin-4-one (4)

To a solution of(E)-3-(4-chlorophenyl)-1-(3-hydroxy-5-methoxypyridin-4-yl)prop-2-en-1-one(3, 20.0 g, 69.2 mmol) in ethanol (500 mL) at 0° C., sodium hydroxide(3.30 g, 83.0 mmol) and 30% aqueous hydrogen peroxide (55.0 mL, 48.4mmol) were added dropwise. The reaction mass was stirred for 30 min at60° C. After completion, the reaction mass was cooled and neutralized bythe addition of 6 M hydrogen chloride to pH ˜7. The solid obtained wasfiltered, washed with cold ethanol, pentane and dried under high vacuumto afford2-(4-chlorophenyl)-3-hydroxy-5-methoxy-4H-pyrano[2,3-c]pyridin-4-one (4)as pale yellow solid. Yield: 4.8 g, 23%; MS (ESI) m/z 304.09[M+1]⁺.

Synthesis of rac-methyl(6R)-7a-(4-chlorophenyl)-5a-hydroxy-4-methoxy-5-oxo-7-phenyl-5a,6,7,7a-tetrahydro-5H-cyclobuta[5,6]pyrano[2,3-c]pyridine-6-carboxylate(6)

A solution of2-(4-chlorophenyl)-3-hydroxy-5-methoxy-4H-pyrano[2,3-c]pyridin-4-one (4,4.80 g, 15.80 mmol) and methyl cinnamate (5, 25.60 g, 158.0 mmol) indichloromethane (200 mL), acetonitrile (100 mL) and methanol (100 mL)was placed in a UV reactor flask. The reaction mixture was irradiatedunder 400 watts UV light for 16 h at 0° C.-15° C. After completion,solvent was removed under reduced pressure and the residue was purifiedover a plug of silica gel eluting the compound with ethyl acetate. Thedesired fractions were concentrated under reduced pressure to affordrac-methyl(6R)-7a-(4-chlorophenyl)-5a-hydroxy-4-methoxy-5-oxo-7-phenyl-5a,6,7,7a-tetrahydro-5H-cyclobuta[5,6]pyrano[2,3-c]pyridine-6-carboxylate(6) as yellow brown solid. Yield: 6.10 g, crude; MS (ESI) m/z466.82[M+1]⁺.

Synthesis of rac-methyl(4bR,6R,7S,7aR)-7a-(4-chlorophenyl)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7)

The crude compound rac-methyl(6R)-7a-(4-chlorophenyl)-5a-hydroxy-4-methoxy-5-oxo-7-phenyl-5a,6,7,7a-tetrahydro-5H-cyclobuta[5,6]pyrano[2,3-c]pyridine-6-carboxylate(6, 6.10 g, 12.90 mmol) was suspended in methanol (60.0 mL) and treatedwith 25% sodium methoxide in methanol (30.0 mL). The reaction was heatedat 80° C. for 3 h. After completion, the solvent was removed underreduced pressure. The crude was diluted with ammonium chloride solutionand extracted with ethyl acetate. The organic phase was separated, driedover anhydrous sodium sulphate and concentrated under reduced pressureto afford rac-methyl(4bR,6R,7S,7aR)-7a-(4-chlorophenyl)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7) Yield: 5.56 g, crude.

Synthesis of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-chlorophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8)

To a solution of rac-methyl(4bR,6R,7S,7aR)-7a-(4-chlorophenyl)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7, 5.50 g, 11.80 mmol) in acetonitrile (55 mL), sodiumtriacetoxyborohydride (15.0 g, 70.09 mmol), and acetic acid (7.0 ml,118.0 mmol) were added. The resulting mixture was stirred for 4 h atroom temperature. After completion, the reaction mixture was partitionedbetween saturated aqueous sodium bicarbonate solution and ethyl acetate.The organic layer was separated, dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to get the crude. Thecrude was purified by silica gel (100-200 mesh size) columnchromatography using 1-5% methanol in dichloromethane as eluent. Thedesired fractions were concentrated under reduced pressure to affordrac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-chlorophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8) as off white solid. Yield: 3.90 g, 71.0%; MS (ESI) m/z 468.40[M+1]⁺.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-chlorophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (9)

To a solution of rac-methyl(4bS,5R,6R,7S,7aR)-7a-(4-chlorophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8, 2.30 g, 4.92 mmol) in methanol: tetrahydrofuran: water (2:1:1, 40mL), lithium hydroxide (1.18 g, 49.20 mmol) was added and the reactionwas stirred for 2 h at room temperature. After completion, the reactionmass was cooled to 0° C. and acidified with 1 M hydrochloric acid to pH˜2-3. The precipitate was filtered and washed with n-pentane and driedunder vacuum to afford rac-(4bS,5R,6R,7S,7aR)-7a-(4-chlorophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (9) as white solid. Yield: 1.90 g, 85%; MS (ESI) m/z 454.19[M+1]⁺.

Synthesis ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-chlorophenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 271F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-chlorophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (9, 0.90 g, 1.98 mmol) in dichloromethane (20 mL) at 0° C.,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidhexafluorophosphate(1.12 g, 2.97 mmol) and N,N-diisopropylethylamine (2.20 mL, 11.88 mmol)were added and the mixture was stirred for 5 min. N,N-dimethylaminehydrochloride (0.80 g, 9.90 mmol) was then added at the same temperatureand the reaction was stirred for 16 h at room temperature. Aftercompletion, the reaction mass was diluted with water, extracted withdichloromethane, dried with anhydrous sodium sulphate, filtered,concentrated to give crude product. The crude product was washed withn-pentane and dried to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-chlorophenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 271F) as white solid. Yield: 0.91 g, 81%; MS (ESI) m/z481.20[M+1]⁺.

Example 272(4bS,5R,6S,7S,7aR)-7a-(4-chlorophenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 272F)

Synthesis of(4bS,5R,6S,7S,7aR)-7a-(4-chlorophenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 272F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-chlorophenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 0.40 g, 0.83 mmol) in dry tetrahydrofuran (8 ml) at 0° C., boranedimethyl sulphide complex (1.60 mL, 16.6 mmol) was added drop wise overa period of 5 min. The reaction mass was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mass was quenched with methanol at 0° C. and heated to refluxfor 48 h. After completion, solvent was removed under reduced pressureand the residue was purified over a plug of silica gel eluting thecompound with 1-5% methanol in dichloromethane. The desired fractionswere concentrated under reduced pressure to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-chlorophenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diolas white solid. Yield: 0.30 g 85%; MS (ESI) m/z 467.42[M+1]⁺. Theenantiomers were separated by chiral SFC [Chiralpak IA (4.6×150) mm,5μ], CO₂/EtOH 60/40 V/V. Peak 1 (Cpd. No. 272F, 120 mg), [α]_(D) −30.0°(c 0.26, CHCl₃), R_(t)=2.977 min, ee: 99.9% MS (ESI) m/z 467.28[M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (s, 1H), 7.95 (s, 1H), 7.20 (d, J=8.56Hz, 2H), 7.09-7.06 (m, 4H), 7.01-6.97 (m, 3H), 5.63 (s, 1H), 5.09 (s,1H), 4.48 (s, 1H), 3.87 (s, 3H), 3.72 (d, J=14.12 Hz 1H), 3.10 (bs, 1H),2.57 (s, 1H), 2.19 (s, 6H), 1.96 (d, J=9.88 Hz, 1H); Peak-2 (110 mg),[α]_(D) +28.4° (c 0.30, CHCl₃), R_(t)=3.483 min, ee: 99.78%, MS (ESI)m/z 467.27[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (s, 1H), 7.95 (s,1H), 7.19 (d, J=8.56 Hz, 2H), 7.09-7.06 (m, 4H), 7.01-6.97 (m, 3H), 5.63(s, 1H), 5.09 (s, 1H), 4.48 (s, 1H), 3.87 (s, 3H), 3.72 (d, J=14.12 Hz1H), 3.10 (bs, 1H), 2.57 (s, 1H), 2.19 (s, 6H), 1.96 (d, J=9.88 Hz, 1H).

Example 273Rac-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(Cpd. No. 273F)

Synthesis ofrac-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(Cpd. No. 273F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.50 g, 3.02 mmol) in dichloromethane (20 mL) at 0° C.,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluorophosphate (1.71 g, 4.52 mmol) and N,N-diisopropylethylamine(3.2 ml, 18.4 mmol) were added and the mixture was stirred for 5 min.6-oxa-3-azabicyclo[3.1.1]heptane (2, 0.613 g, 4.52 mmol) was then addedat the same temperature and the reaction was stirred for 16 h at roomtemperature. After completion, the reaction mixture was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel (100-200 mesh size) column chromatography using 0-5% methanolin dichloromethane as eluent. The desired fractions were concentrated toaffordrac-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(Cpd. No. 273F) as white solid. Yield: 1.5 g, 88%; MS (ESI) m/z579.21[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 8.11 (s, 1H), 8.05 (s, 1H),7.22-7.19 (m, 2H), 7.11-7.00 (m, 4H), 6.99-6.93 (m, 3H), 5.70 (d, J=15.8Hz, 1H), 5.23-5.20 (m, 1H), 4.85-4.79 (m, 1H), 4.74-4.69 (m, 1H),4.59-4.50 (m, 2H), 4.45 (t, J=26.8 Hz, 1H), 4.15-4.04 (m, 1H), 4.01-3.92(m, 1H), 3.87 (d, J=5.32 Hz, 3H), 3.57 (d, J=13.92 Hz, 1H), 3.40-3.37(m, 1H), 3.10 (t, J=7.24 Hz, 1H), 1.88 (m, 1H).

Example 2744-((4bS,5R,6S,7S,7aR)-6-((6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 274F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-6-((6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (2)

To a solution ofrac-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5Hcyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone(1, 1.30 g, 2.22 mmol) in dry tetrahydrofuran (20 ml) at 0° C., boranedimethyl sulphide complex (5.0 ml, 44.9 mmol) was added dropwise over aperiod of 5 min. The reaction mixture was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mixture was quenched with methanol at 0° C. and heated toreflux for 5 h. After completion, solvent was removed under reducedpressure and the residue was purified by silica gel (100-200 mesh size)using 5% methanol in dichloromethane as eluent. The desired fractionswere concentrated under reduced pressure to affordrac-(4bS,5R,6S,7S,7aR)-6-((6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 0.3 g, (crude); MS (ESI) m/z 567.39[M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-6-((6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 274F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-6-((6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.3 g, 0.53 mmol) in N,N-dimethylformamide (3 mL), zinc cyanide (0.3g, 2.65 mmol) and zinc dust (0.004 g, 0.063 mmol) were added at roomtemperature and the reaction mixture was degassed with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.006 g, 0.0106 mmol) andtris(dibenzylideneacetone)dipalladium (0.015 g, 0.016 mmol) were addedto the reaction, degassed for additional 5 min and mixture was heated at130° C. for 4 h. After completion, the reaction mixture was diluted withethyl acetate and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel (100-200 mesh size) column chromatography using 2-3% methanolin dichloromethane as eluent. The desired fractions were concentrated toaffordrac-4-((4bS,5R,6S,7S,7aR)-6-((6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.04 g, 15%; MS (ESI) m/z 511.86[M+1]⁺. Theenantiomers were separated by chiral HPLC [Chiralpak IG (4.6×250) mm, 5μm] in hexane/EtOH=50/50 (v/v). Peak 1 (Cpd. No. 274F, 3 mg),R_(t)=8.073 min, ee: 99.86%; MS (ESI) m/z 511.86[M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) 8.05 (s, 1H), 7.97 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.37 (d,J=8.4 Hz, 2H), 7.10-6.98 (m, 5H), 5.75 (s, 1H), 5.13 (d, J=5.2 Hz, 1H),4.53 (bs, 1H), 4.49 (bs, 1H), 4.39 (s, 1H), 3.87 (s, 3H), 3.82 (s, 1H),3.33 (s, 2H), 3.09 (d, J=11.6 Hz, 1H), 2.89-2.77 (m, 2H), 2.64-2.54 (m,2H), 2.40-2.24 (m, 2H). Peak-2 (3 mg), R_(t)=11.833 min, ee: 99.94%; MS(ESI) m/z 512.27[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) 8.05 (s, 1H), 7.97 (s,1H), 7.49 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.10-6.98 (m, 5H),5.75 (s, 1H), 5.13 (d, J=5.2 Hz, 1H), 4.53 (bs, 1H), 4.49 (bs, 1H), 4.39(s, 1H), 3.87 (s, 3H), 3.82 (s, 1H), 3.33 (s, 2H), 3.09 (d, J=11.6 Hz,1H), 2.89-2.77 (m, 2H), 2.64-2.54 (m, 2H), 2.40-2.24 (m, 2H).

Example 275Rac-(3aR,4S,4aR,9bS,9cR)-4a-(4-bromophenyl)-9b-hydroxy-9-methoxy-4-phenyl-3,3a,4,4a,9b,9c-hexahydro-2H-furo[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-2-one(Cpd. No. 275F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 5.0 g, 10.03 mol) in dry tetrahydrofuran (100 mL) at 0° C.,borane dimethyl sulphide complex (9.52 mL, 100.33 mmol) was added dropwise over a period of 5 min. The reaction mixture was heated at 60° C.for 6 h. After completion, the reaction mass was quenched with methanolat 0° C. and heated to reflux for 16 h. After completion, solvent wasremoved under reduced pressure to get the crude. The crude productobtained was triturated with diethyl ether, filtered and dried undervacuum to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 4.5 g, 93%; MS (ESI) m/z 484.3[M+1]⁺.

Synthesis ofrac-((4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methylmethanesulfonate (3)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 4.5 g, 9.29 mmol) in pyridine (90 mL) at 0° C., methane sulfonylchloride (1.60 g, 19.93 mmol) was added. The resulting mixture wasstirred at room temperature for 16 h. After completion, the solvent wasremoved under reduced pressure. The crude was diluted with water andextracted with ethyl acetate. The organic layer was separated, driedover anhydrous sodium sulphate and concentrated under reduced pressureto afford crude product. The crude product was purified by silica gel(100-200 mesh size) column chromatography using 5% methanol indichloromethane as eluents. The desired fractions were concentratedunder reduced pressure to affordrac-((4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methylmethanesulfonate (3) as white solid. Yield: 4.20 g, 80.0%; MS (ESI) m/z562.3 [M+1]⁺.

Synthesis ofrac-2-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)acetonitrile(4)

To a solution ofrac-((4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methylmethanesulfonate (3, 4.20 g, 7.47 mmol) in dimethylsulfoxide (84 mL),potassium cyanide (4.86 g, 74.6 mmol) was added. The resulting mixturewas heated at 80° C. for 16 h. After completion, the reaction mixturewas diluted with water and extracted with ethyl acetate. The organiclayer was washed with ice cold water and brine. The organic layer wasseparated, dried over anhydrous sodium sulphate and concentrated underreduced pressure to afford crude product. The crude product was purifiedby silica gel (100-200 mesh size) column chromatography using 5%methanol in dichloromethane as eluents. The desired fractions wereconcentrated under reduced pressure to affordrac-2-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)acetonitrile(4) as yellow brown solid. Yield: 2.1 g, 58%. MS (ESI) m/z 493.33[M+1]⁺.

Synthesis ofrac-2-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)aceticacid (5)

In a sealed tube to a solution ofrac-2-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)acetonitrile(4, 0.8 g, 1.6 mol) in tetrahydrofuran (4 mL), 10% aqueous sodiumhydroxide solution (16 mL) was added. The reaction mixture was heated at125° C. for 36 h. After completion, the reaction mixture was acidifiedusing 1N hydrochloric acid, the solid was precipitated and filtered. Thecrude product obtained was triturated with diethyl ether and dried undervacuum to affordrac-2-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)aceticacid (5) as white solid. Yield: 0.75 g, 90%; MS (ESI) m/z 512.3[M+1]⁺.

Synthesis ofrac-(3aR,4S,4aR,9bS,9cR)-4a-(4-bromophenyl)-9b-hydroxy-9-methoxy-4-phenyl-3,3a,4,4a,9b,9c-hexahydro-2H-furo[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-2-one(Cpd. No. 275F)

To a solution ofrac-2-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)aceticacid (5, 0.45 g, 0.88 mmol) in dichloromethane (9 mL) at 0° C.,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.50 g, 2.63 mmol),hydroxybenzotriazole (0.40 g, 2.63 mmol) and N,N-diisopropylethylamine(1.09 mL, 6.15 mmol) were added and the mixture was stirred for 5 min.dimethylamine hydrochloride (0.358 g, 4.39 mmol) was then added at thesame temperature and the reaction was stirred for 16 h at roomtemperature. After completion, the reaction mass was diluted withdichloromethane and washed with cold water. The organic layer wasseparated and dried over sodium sulphate, filtered and concentrated togive crude. The crude was purified by silica gel 100-200 mesh size)column chromatography using 3% methanol in dichloromethane as eluent.The desired fractions were concentrated to affordrac-3aR,4S,4aR,9bS,9cR)-4a-(4-bromophenyl)-9b-hydroxy-9-methoxy-4-phenyl-3,3a,4,4a,9b,9c-hexahydro-2H-furo[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-2-one(Cpd. No. 275F) as off white solid. Yield: 0.40 g, 66.0%; MS (ESI) m/z494.31[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (s, 1H), 8.12 (s, 1H),7.35 (d, J=8.36 Hz, 2H), 7.12-7.10 (m, 5H), 6.96 (d, J=5.04, 2H), 6.02(s, 1H), 5.36 (d, J=6.48 Hz, 1H), 3.96 (s, 3H), 3.80-3.74 (m, 1H), 3.37(s, 1H), 2.90 (dd, J=17.88 Hz, 7.94 Hz, 1H), 1.99 (d, J=17.8, 1H).

Example 276Rac-4-((4bS,5R,6R,7S,7aR)-6-(2-(dimethylamino)ethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 276F)

Synthesis ofrac-2-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)-N,N-dimethylacetamide(2)

To a solution ofrac-(3aR,4S,4aR,9bS,9cR)-4a-(4-bromophenyl)-9b-hydroxy-9-methoxy-4-phenyl-3,3a,4,4a,9b,9c-hexahydro-2H-furo[3″,2″:4′,5′]cyclopenta[1′,2′:4,5]furo[2,3-c]pyridin-2-one(1, 0.25 g, 0.506 mol) in 2M solution of dimethyl amine (20 mL) intetrahydrofuran, 50% propylphosphonicanhydride solution in ethyl acetate(3.2 mL, 5.05 mmol) was added. The reaction mixture was heated at 80° C.for 16 h. After completion the reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was washed withbrine. The organic layer was separated, dried over anhydrous sodiumsulphate and concentrated under reduced pressure to afford crudeproduct. The crude product was purified by silica gel (100-200 meshsize) column chromatography using 5% methanol in dichloromethane aseluent. The desired fractions were concentrated under reduced pressureto affordrac-2-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)-N,N-dimethylacetamide(2) as white solid. Yield: 0.13 g, 48%. MS (ESI) m/z 539.43[M+1]⁺.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(2-(dimethylamino)ethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3)

To a solution ofrac-2-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)-N,N-dimethylacetamide(2, 0.13 g, 0.24 mmol) in dry tetrahydrofuran (5.2 ml) at 0° C., boranedimethyl sulphide complex (0.23 ml, 2.4 mmol) was added drop wise over aperiod of 5 min. The reaction mixture was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mixture was quenched with methanol (40 ml) at 0° C. and heatedto reflux for 24 h. After completion, solvent was removed under reducedpressure and crude obtained was purified by silica gel (100-200 meshsize) column chromatography using 10% methanol in dichloromethane aseluent. The desired fractions were concentrated under reduced pressureto affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(2-(dimethylamino)ethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3). Yield: 0.09 g, 69%; MS (ESI) m/z 525.4[M+1]⁺.

Synthesis ofrac-4-((4bS,5R,6R,7S,7aR)-6-(2-(dimethylamino)ethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 276F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(2-(dimethylamino)ethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3, 0.09 g, 0.171 mmol) in N,N-dimethylformamide (4 mL), zinc cyanide(0.12 g, 1.03 mmol) and zinc dust (0.00013 g, 0.002 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15minutes. 1,1′-Bis(diphenylphosphino)ferrocene (0.0018 g, 0.00342 mmol)and Tetrakis(triphenylphosphine)palladium (0.0046 g, 0.00513 mmol) wereadded to the reaction mixture, degassed for additional 5 min and mixturewas heated at 140° C. for 8 h. After completion, the reaction mixturewas diluted with ethyl acetate and washed with cold water. The organiclayer was separated and dried over anhydrous sodium sulphate, filteredand concentrated to give crude product. The crude product was purifiedby silica gel (100-200 mesh size) column chromatography using 6%methanol in dichloromethane as eluent. The desired fractions wereconcentrated to affordrac-4-((4bS,5R,6R,7S,7aR)-6-(2-(dimethylamino)ethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 276F) as white solid. Yield: 0.015 g, 18%; MS (ESI) m/z472.28[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 8.05 (s, 1H), 7.97 (s, 1H), 7.50(d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.09-7.05 (m, 2H), 7.01-6.96(m, 3H), 5.68 (s, 1H), 4.42 (d, J=4.04 Hz, 1H), 3.88 (s, 3H), 3.76 (d,J=14.1 Hz, 1H), 3.03 (bs, 1H), 2.41-2.37 (m, 1H), 2.32-2.26 (m, 1H),2.12 (s, 6H), 1.48 (bs, 1H), 1.41 (bs, 1H).

Example 277Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-N-(pyridin-3-ylmethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 277F)

Synthesis of N-methyl-1-(pyridin-3-yl)methanamine (2)

To a solution of nicotinaldehyde (1, 1.50 g, 14 mmol) in methanol (30ml) 2.0 M methylamine (21 ml, 42 mmol) in tetrahydrofuran was added andthe reaction was stirred for 16 h at room temperature. Sodiumborohydride (0.53 g, 14 mmol) was added portion wise at 0° C. and thereaction was stirred for 6 h at room temperature. After completion, thereaction mass was concentrated to give crude product. The crude productwas triturated with pentane, supernent layer was decanted off at 0° C.and the residue was dried under vacuum to affordN-methyl-1-(pyridin-3-yl) methanamine (2) as brown oil. Yield: 1.4 g(Crude) MS (ESI) m/z 123.05[M+1]⁺.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-N-(pyridin-3-ylmethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 277F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (3, 1.50 g, 3.02 mmol) in N,N-dimethylformamide (20 mL) at 0° C.,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluorophosphate (1.71 g, 4.52 mmol), and N,N-diisopropylethylamine(3.20 ml, 18.4 mmol) were added and the mixture was stirred for 5 min.N-methyl-1-(pyridin-3-yl)methanamine (2, 1.1 g, 9.03 mmol) was thenadded at the same temperature and the reaction was stirred for 16 h atroom temperature. After completion, the reaction mixture was dilutedwith dichloromethane and washed with cold water. The organic layer wasseparated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude. The crude was purified by silica gel(100-200 mesh size) column chromatography using 0-5% methanol indichloromethane as eluent. The desired fractions were concentrated toaffordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-N-(pyridin-3-ylmethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 277F) as white solid. Yield: 1.30 g, 72%; MS (ESI) m/z602.37[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆)(Compound exist in rotamericform) 8.65-8.42 (m, 2H), 8.11 (d, J=7.6 Hz, 1H), 8.01 (s, 1H), 7.80-7.54(m, 1H), 7.31-6.68 (m, 9H), 5.77-5.71 (m, 1H), 5.29-5.23 (m, 1H),4.86-4.80 (m, 1H), 4.58-4.40 (m, 2H), 4.28 (dd, J=13.72 Hz, 5.32 Hz,1H), 3.89 (s, 3H), 3.26-2.77 (m, 4H).

Example 2784-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl(pyridin-3-ylmethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 278F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methyl(pyridin-3-ylmethyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-methyl-7-phenyl-N-(pyridin-3-ylmethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 1.25 g, 2.07 mmol) in dry tetrahydrofuran (25 ml) at 0° C., boranedimethyl sulphide complex (2.0 ml, 20.7 mmol) was added drop wise over aperiod of 5 min. The reaction mass was slowly brought to roomtemperature and stirred for additional 6 h. After completion, thereaction mass was quenched with methanol at 0° C. and heated to refluxfor 5 h. After completion, solvent was removed under reduced pressureand the residue was purified over a plug of silica gel (100-200 meshsize) using 5% methanol in dichloromethane as eluent. The desiredfractions were concentrated under reduced pressure to affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methyl(pyridin-3-ylmethyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2) as white solid. Yield: 0.65 g; MS (ESI) m/z 588.45[M+1]⁺. Synthesisof4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl(pyridin-3-ylmethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 278F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-((methyl(pyridin-3-ylmethyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.650 g, 0.72 mmol) in N,N-dimethylformamide (5 mL), zinc cyanide(0.127 g, 1.079 mmol) and zinc dust (0.005 g, 0.072 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15min. 1,1′-Bis(diphenylphosphino)ferrocene (0.053 g, 0.072 mmol) andtris(dibenzylideneacetone)dipalladium (0.020 g, 0.021 mmol) were addedto the reaction mixture, degassed for additional 5 min and mixture washeated at 140° C. for 3 h. After completion, the reaction mixture wasdiluted with ethyl acetate and washed with cold water. The organic layerwas separated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel (100-200 mesh size) column chromatography using 5-10%methanol in dichloromethane as eluent. The desired fractions wereconcentrated to affordrac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl(pyridin-3-ylmethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.350 g, 47%; The enantiomers were separated bychiral HPLC [Chiralpak IG (4.6×250) mm, 5 μm] in n-hexane/EtOH=50/50(v/v). Peak 1 (77 mg), [α]_(D) −539° (c 0.11, CHCl₃), R_(t)=7.188 min,ee: 99.60%; MS (ESI) m/z 534.99[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 8.55(s, 1H), 8.47 (d, J=3.3 Hz, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 7.75 (d,J=8.04 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.37-7.35 (m, 3H), 7.06-6.96 (m,5H), 5.77 (s, 1H), 5.16 (d, J=5.2 Hz, 1H), 4.59 (t, J=4.0 Hz, 1H), 3.90(s, 3H), 3.78 (d, J=14.24 Hz, 1H), 3.68 (d, J=13.4 Hz, 1H), 3.42 (d,J=13.44 Hz, 1H), 3.32-3.23 (m, 1H), 2.72-2.66 (m, 1H), 2.19 (s, 4H);Peak-2 (Cpd. No. 278F, 85 mg), [α]_(D) +554.1° (c 0.11, CHCl₃)R_(t)=13.72 min, ee: 99.84%; MS (ESI) m/z 534.90[M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) 8.55 (s, 1H), 8.46 (d, J=3.3 Hz, 1H), 8.05 (s, 1H), 7.98 (s,1H), 7.75 (d, J=8.04 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.37-7.35 (m, 3H),7.06-6.96 (m, 5H), 5.77 (s, 1H), 5.16 (d, J=5.2 Hz, 1H), 4.60 (t, J=4.0Hz, 1H), 3.90 (s, 3H), 3.78 (d, J=14.24 Hz, 1H), 3.68 (d, J=13.4 Hz,1H), 3.42 (d, J=13.44 Hz, 1H), 3.32-3.23 (m, 1H), 2.72-2.66 (m, 1H),2.19 (s, 4H).

Example 279Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(3,3-difluoropyrrolidin-1-yl)methanone(Cpd. No. 279F)

Synthesis ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(3,3-difluoropyrrolidin-1-yl)methanone (Cpd. No. 279F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 2.0 g, 4.0 mmol) in dichloromethane (50 mL) at 0° C. were added3,3-difluoropyrrollidine hydrochloride (2, 0.86 g, 6.0 mmol)N,N-diisopropylethylamine (2.5 ml,16.0 mmol) and propylphosphonicanhydride (T₃P, 6 ml, 10 mmol). The reaction mixture was stirred at roomtemperature for overnight. After completion, saturated solution ofsodium bicarbonate was added to reaction mixture and concentrated toremove dichloromethane. The solid precipitated was filtered off. Thecrude product was purified by combi-flash (12 g, RediSep column) using0-5% methanol in dichloromethane as eluent. The desired fractions wereconcentrated under reduced pressure to affordrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(3,3-difluoropyrrolidin-1-yl)methanone(Cpd. No. 279F) as white solid. Yield: 0.64 g, 34%; MS (ESI) m/z 587.4[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 1H), 7.99 (s, 1H),7.20-7.18 (m, 2H), 7.11-7.02 (m, 4H), 6.93 (bs, 3H), 5.69 (d, J=10.0 Hz,1H), 5.21 (bs, 1H), 4.80-4.76 (m, 1H), 4.65-4.30 (m, 2H), 4.13-4.02 (m,2H), 3.88 (s, 3H), 3.68-3.57 (m, 1H), 3.47 (t, J=7.3 Hz, 1H), 2.65 (bs,1H), 2.38 (bs, 1H).

Example 2804-((4bS,5R,6S,7S,7aR)-6-((3,3-difluoropyrrolidin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 280F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((3,3-difluoropyrrolidin-1-yl)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (2)

To a solution ofrac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(3,3-difluoropyrrolidin-1-yl)methanone(1, 0.630 g, 1.0 mmol) in tetrahydrofuran (15 ml) at 0° C., boranedimethylsulfide (1.02 mL, 10.0 mmol) was added. The reaction mixture wasstirred at room temperature for overnight. After completion, reactionmixture was quenched with methanol at 0° C. and then heated at 70° C.for 6 h. The solvents were concentrated and the residue was purified byflash column chromatography by eluting with gradient of 0-5% methanol indichloromethane to affordrac-((4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((3,3-difluoropyrrolidin-1-yl)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol)(2) as white solid. Yield: 0.4 g, 65%; MS (ESI) m/z 573.4[M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-6-((3,3-difluoropyrrolidin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 280F)

To a mixture ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((3,3-difluoropyrrolidin-1-yl)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(2, 0.4 g, 0.69 mmol) in N,N-dimethylformamide (5.0 mL) at roomtemperature were added, zinc cyanide (245 mg, 2.09 mmol) and zinc (65mg, 0.69 mmol), and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino) ferrocene (38 mg, 0.07 mmol) andtris(dibenzylideneacetone)dipalladium (32 mg, 0.035 mmol) were added tothe reaction mixture and degassing was continued for another 5 min. Thereaction mixture was heated at 140° C. for 6 h. After completion, thereaction mixture was cooled to room temperature and passed throughcelite bed. The filtrate was concentrated and treated with ice-coldwater, the solid precipitated was filtered. The crude product waspurified by combi-flash (12 g RediSep column) using 5% methanol anddichloromethane as eluent. The product obtained was repurified byreverse phase preparative HPLC. The desired fractions were lyophilizedto affordrac-4-((4bS,5R,6S,7S,7aR)-6-((3,3-difluoropyrrolidin-1-yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.20 g, 55%. The enantiomers were separated bychiral SFC [Chiralpak IA (4.6×250) mm, 5μ] using CO₂/MeOH=(80/20), Peak1 (Cpd. No. 280F, 50 mg), [α]_(D) +22.9° (c 0.27, CHCl₃), R_(t)=3.73min, ee 99.66%; MS (ESI) m/z 520.30 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ8.04 (s, 1H), 7.97 (s, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.4 Hz,2H), 7.09-6.97 (m, 5H), 5.77 (s, 1H), 5.18 (d, J=5.3 Hz, 1H), 4.50 (t,J=4.52 Hz, 1H), 3.87 (s, 3H), 3.78 (d, J=14.0 Hz, 1H), 3.18-3.12 (m,2H), 2.91-2.61 (m, 4H), 2.32-2.17 (m, 3H). Peak-2 (49 mg), [α]_(D)−15.0° (c 0.25, CHCl₃), R_(t)=6.34 min, ee 99.84%; MS (ESI) m/z 520.28[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.97 (s, 1H), 7.48 (d,J=8.3 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 7.09-6.97 (m, 5H), 5.77 (s, 1H),5.18 (d, J=5.2 Hz, 1H), 4.50 (t, J=4.72 Hz, 1H), 3.87 (s, 3H), 3.78 (d,J=14.2 Hz, 1H), 3.19-3.11 (m, 2H), 2.91-2.66 (m, 4H), 2.30-2.19 (m, 3H).

Example 281Rac-((4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(morpholino)methanone(Cpd. No. 281F)

Synthesis of(E)-1-(3-hydroxy-5-methoxypyridin-4-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(3)

To a solution of 1-(3-hydroxy-5-methoxypyridin-4-yl)ethan-1-one (1, 20.0g, 11.97 mmol) in methanol (100 mL) at 0° C. were added sodium hydroxide(5.70 g, 14.37 mmol) and 4-(trifluoromethyl)benzaldehyde (2, 20.8 g,11.97 mmol). The reaction mixture was then stirred at 70° C. for 15 min.After completion, reaction mixture was cooled to 0° C. and water wasadded and neutralized to pH ˜7 with 6 M aqueous hydrogen chloride. Thesolid obtained was filtered, washed with excess of water and dried undervacuum to afford(E)-1-(3-hydroxy-5-methoxypyridin-4-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(3) as yellow solid. Yield: 31.0 g; MS (ESI) m/z 322.18[M−1]⁻.

Synthesis of3-hydroxy-5-methoxy-2-(4-(trifluoromethyl)phenyl)-4H-pyrano[2,3-c]pyridin-4-one(4)

To a solution of(E)-1-(3-hydroxy-5-methoxypyridin-4-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(3, 25.0 g, 77.4 mmol) in methanol (250 mL) was added crushed sodiumhydroxide (3.71 g, 92.8 mmol) followed by addition of hydrogen peroxide(44.0 mL, 387.0 mmol) at 0° C. The reaction mixture was stirred for 45min at room temperature. After completion, reaction mixture wasneutralized with 6 M hydrogen chloride to pH ˜7. The solid obtained wasfiltered and dried under vacuum to afford3-hydroxy-5-methoxy-2-(4-(trifluoromethyl)phenyl)-4H-pyrano[2,3-c]pyridin-4-one(4) as pale yellow solid. Yield: 5.50 g, 21%; MS (ESI) m/z 336.18[M−1]⁻.

Synthesis of rac-methyl(2S,3S,4S,5R)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2-(4-(trifluoromethyl)phenyl)-2,3,4, 5-tetrahydro-2, 5-methanooxepino[2,3-c]pyridine-4-carboxylate (6)

A solution of 3-hydroxy-5-methoxy-2-(4-(trifluoromethyl)phenyl)-4H-pyrano [2,3-c]pyridin-4-one (4, 5.50 g, 16.3 mmol) and methylcinnamate (5, 26.4 g, 163.3 mmol) in dichloromethane (200 mL),acetonitrile (100 mL) and methanol (100 mL) was placed in a UV reactorflask. The reaction mixture was irradiated for 16 h under 400 watts UVlight at 0-15° C. After completion, the solvent was removed underreduced pressure and the crude residue was purified by Combi-flash (40g, RediSep column) by using ethyl acetate as eluent. The desiredfractions were concentrated under reduced pressure to afford rac-methyl(2S,3S,4S,5R)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(6) as brown solid. Yield: 6.0 g, crude.

Synthesis of rac-methyl (4bR,6R,7S,7aR)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7)

The crude rac-methyl(2S,3S,4S,5R)-5-hydroxy-6-methoxy-10-oxo-3-phenyl-2-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-2,5-methanooxepino[2,3-c]pyridine-4-carboxylate(6, 6.0 g) was suspended in methanol (60 mL) and treated with sodiummethoxide (25% in methanol, 60 mL) and heated the mixture to 80° C. for3 h. After completion, the solvent was removed under reduced pressureand mixture was diluted with ammonium chloride solution and extractedwith ethyl acetate. The organic phase was separated, dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure to afford rac-methyl(4bR,6R,7S,7aR)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7) as brown solid. Yield: 5.90 g, crude.

Synthesis of rac-methyl(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8)

To a solution of rac-methyl(4bR,6R,7S,7aR)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(7, 5.9 g, 11.8 mmol) in acetonitrile (60 mL) and acetic acid (7.1 mL,118.0 mmol) was added sodium triacetoxyborohydride (15.0 g, 70.8 mmol).The resulting mixture was stirred at room temperature for 4 h. Aftercompletion, reaction mixture was partitioned between saturated aqueoussodium bicarbonate solution and ethyl acetate. The organic layer wasseparated, dried over anhydrous sodium sulphate and concentrated underreduced pressure to get the crude residue. The crude residue waspurified by combi-flash (40 g, RediSep) using 30-50% ethyl acetate inhexane as eluent. The desired fractions were concentrated under reducedpressure to afford rac-methyl(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8) as off white solid. Yield: 3.50 g, 58.10%; MS (ESI) m/z500.55[M−1]⁻.

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (9)

To a solution of rac-methyl(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(8, 3.50 g, 6.18 mmol) in methanol and water (3:1, 30 mL), lithiumhydroxide (1.48 g, 61.8 mmol) was added and the reaction was stirred atroom temperature for 1 h. After completion, methanol was distilled offand reaction mixture was cooled to 0° C., acidified with 1 M hydrogenchloride to pH ˜6. The precipitated solid was filtered and dried undervacuum to affordrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (9) as off white solid. Yield: 2.80 g, 82%; MS (ESI) m/z486.47[M−1]⁻.

Synthesis ofrac-((4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(morpholino)methanone(Cpd. No. 281F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (9, 0.65 g, 1.3 mmol) in N,N-dimethylformamide (5 mL),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (1.0 g, 2.6 mmol) and N,N-diisopropylethylamine (0.7ml, 4.0 mmol) were added at 0° C. and stirred the mixture for 5 min.morpholine (0.17 g, 2.0 mmol) was then added and the reaction mixturewas stirred for 3 h at 25° C. After completion, reaction mixture wasdiluted with ethyl acetate and washed with cold water. The organic layerwas dried over anhydrous sodium sulphate, filtered and concentrated togive crude product. The crude product was purified by Combi-flash (12 g,RediSep column) using 6% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-((4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(morpholino)methanone(Cpd. No. 281F) as off white solid. Yield: 0.7 g, 94%; MS (ESI) m/z556.89 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (s, 1H), 8.01 (s, 1H),7.36 (s, 4H), 7.03-7.00 (m, 2H), 6.95-6.92 (m, 3H), 5.78 (s, 1H), 5.29(d, J=5.4 Hz, 1H), 4.72 (t, J=5.2 Hz, 1H), 4.50 (d, J=13.4 Hz, 1H), 4.26(dd, J=5.08, 13.2 Hz, 1H), 3.88 (s, 4H), 3.79-3.47 (m, 7H).

Example 282(4bS,5R,6S,7S,7aR)-4-methoxy-6-(morpholinomethyl)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 282F)

Synthesis of(4bS,5R,6S,7S,7aR)-4-methoxy-6-(morpholinomethyl)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 282F)

To a solution ofrac-((4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(morpholino)methanone(1, 0.7 g, 1.25 mmol) in tetrahydrofuran (10 mL), Borane dimethylsulphide (1.0 mL, 12.5 mmol) was added at 0° C. and stirred the mixturefor 6 h at 70° C. After completion, reaction mixture was quenched withmethanol (10.0 mL) at 0° C. and again heated for 10 h at 80° C. Thereaction mixture was concentrated to give crude product. The crudeproduct was purified by combi-flash (12 g, RediSep column) using 20%methanol in dichloromethane as eluent. The desired fractions wereconcentrated under reduced pressure. The compound was again re-purifiedby reverse phase preparative HPLC and desired fractions were lyophilizedto giverac-(4bS,5R,6S,7S,7aR)-4-methoxy-6-(morpholinomethyl)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diolas white solid. Yield: 50 mg, 7%. The enantiomers were separated bychiral SFC [Chiralpak IG (4.6×250) mm, 5μ]; CO₂/0.1% TEA in EtOH=(80/20)Peak 1 (Cpd. No. 282F, 12 mg), [α]_(D) −70.0° (c 0.26, CHCl₃),R_(t)=5.19 min, ee: 99.76%; MS (ESI) m/z 543.31 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d6) δ 8.04 (s, 1H), 7.96 (s, 1H), 7.39 (bs, 4H), 7.04-7.00 (m, 5H),5.70 (s, 1H), 5.08 (bs, 1H), 4.52 (s, 1H), 3.87 (s, 3H), 3.78 (d, J=14.7Hz, 1H), 3.61-3.50 (m, 6H), 2.32-1.89 (m, 5H); Peak 2 (8 mg), [α]_(D)+50.2° (c 0.25, CHCl₃), R_(t)=7.89 min, ee: 99.70%; MS (ESI) m/z 543.31[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.04 (s, 1H), 7.96 (s, 1H), 7.39(d, J=7.88 Hz, 4H), 7.06-7.00 (m, 5H), 5.70 (s, 1H), 5.08 (bs, 1H), 4.52(s, 1H), 3.88 (s, 3H), 3.78 (d, J=14.0 Hz, 1H), 3.61-3.22 (m, 6H),2.62-2.05 (m, 5H).

Example 283Rac-(4bS,5R,6S,7S,7aR)-4-methoxy-6-((4-methylpiperazin-1-yl)methyl)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 283F)

Synthesis ofrac-((4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4-methylpiperazin-1-yl)methanone(Cpd. No. 283F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 1.0 g, 1.0 mmol) in N,N-dimethylformamide (20 mL) at 0° C. wereadded1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluorophosphate (1.2 g, 3.0 mmol) and N,N-diisopropylethylamine (0.8ml, 5.1 mmol) and reaction mixture stirred for 5 min. 1-methylpiperazine(2, 0.25 g, 2.5 mmol) was then added and the reaction mixture wasstirred for 2 h at 25° C. After completion, reaction mixture was dilutedwith ethyl acetate and washed with cold water. The organic layer wasdried over anhydrous sodium sulphate, filtered and concentrated to givecrude product. The crude product was purified by combi-flash (12 g,RediSep column) using 6% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-((4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4-methylpiperazin-1-yl)methanone(Cpd. No. 283F) as white solid. Yield: 0.55 g, 94%; MS (ESI) m/z 570.29[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 1H), 8.00 (s, 1H), 7.35 (s,4H), 7.03-7.00 (m, 2H), 6.95-6.90 (m, 3H), 5.79 (s, 1H), 5.22 (d, J=5.3Hz, 1H), 4.70 (t, J=5.1 Hz, 1H), 4.52 (d, J=13.4 Hz, 1H), 4.26 (dd,J=4.7, 13.2 Hz, 1H), 3.87 (s, 4H), 3.67 (bs, 1H), 3.48 (bs, 1H), 3.32(bs, 1H), 2.54 (bs, 1H), 2.37-2.32 (m, 2H), 2.23 (s, 3H), 2.11 (bs, 1H).

Example 284(4bS,5R,6S,7S,7aR)-4-methoxy-6-((4-methylpiperazin-1-yl)methyl)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 284F)

Synthesis of(4bS,5R,6S,7S,7aR)-4-methoxy-6-((4-methylpiperazin-1-yl)methyl)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 284F)

To a solution ofrac-((4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4-methylpiperazin-1-yl)methanone(1, 0.5 g, 0.87 mmol) in tetrahydrofuran (10 mL) at 0° C., boranedimethyl sulphide (0.7 mL, 8.7 mmol) was added and reaction mixture wasstirred for 3 h at room temperature. After completion, reaction mixturewas quenched with methanol (5.0 mL) at 0° C. and heated for 10 h at 60°C. The reaction mixture was concentrated to give crude product. Thecrude product was purified by combi-flash (12 g, RediSep column) using20% methanol in dichloromethane as eluent. The desired fractions wereconcentrated under reduced pressure. The compound was re-purified byreverse phase preparative HPLC and desired fractions were lyophilized togiverac-(4bS,5R,6S,7S,7aR)-4-methoxy-6-((4-methylpiperazin-1-yl)methyl)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diolas white solid. Yield: 0.210, 48%. The enantiomers were separated bychiral SFC [Chiralpak IA (4.6×250) mm, 5μ]; CO₂/0.1% TEA in MeOH=60/40],Peak 1 (Cpd. No. 284F, 17 mg), [α]_(D) −48.1° (c 0.27, CHCl₃),R_(t)=1.54, ee 99.90%; MS (ESI) m/z 556.33 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ: 8.02 (s, 1H), 7.94 (s, 1H), 7.39-7.34 (m, 4H), 7.05-7.02 (m,2H), 6.98-6.96 (m, 3H), 5.68 (s, 1H), 5.06 (bs, 1H), 4.47 (s, 1H), 3.85(s, 3H), 3.76 (d, J=14.2, 1H), 3.22-3.19 (m, 1H), 2.60-2.57 (m, 4H),2.30 (m, 5H), 2.15 (s, 3H), 2.06 (d, J=11.48 Hz, 1H); Peak 2 (16 mg),[α]_(D) +14.8° (c 0.25, CHCl₃), R_(t)=2.55, ee 99.9%; MS (ESI) m/z556.32 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.04 (s, 1H), 7.96 (s, 1H),7.41-7.36 (m, 4H), 7.07-7.04 (m, 2H), 7.00-6.98 (m, 3H), 5.70 (s, 1H),5.08 (bs, 1H), 4.49 (s, 1H), 3.87 (s, 3H), 3.78 (d, J=14.2, 1H),3.24-3.22 (m, 1H), 2.59-2.56 (m, 4H), 2.32 (bs, 5H), 2.16 (s, 3H), 2.02(d, J=11.12 Hz, 1H).

Example 285Rac-(4bS,5R,6R,7S,7aR)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 285F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 285F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 0.7 g, 1.0 mmol) in N,N-dimethylformamide (5.0 mL),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (1.60 g, 4.3 mmol) and N,N-diisopropylethylamine(1.25 ml, 7.1 mmol) were added at 0° C. and stirred the mixture for 5min. 2,2-Difluoroethan-1-amine (2, 0.20 mL, 2.8 mmol) was then added andthe reaction mixture was stirred for 2 h at 25° C. After completion,reaction mixture was diluted with ethyl acetate and washed with coldwater. The organic layer was dried over anhydrous sodium sulphate,filtered and concentrated to give crude product. The crude product waspurified by combi-flash (12 g, RediSep column) using 6% methanol indichloromethane as eluent. The desired fractions were concentrated toaffordrac-(4bS,5R,6R,7S,7aR)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(Cpd. No. 285F) as white solid. Yield: 0.66 g, 83%; MS (ESI) m/z 551.18[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (t, J=5.5 Hz, 1H), 8.12 (s,1H), 7.99 (s, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.2 Hz, 2H),7.04-7.01 (m, 2H), 6.96 (bs, 3H), 6.05-5.75 (m, 2H), 5.13 (d, J=4.5 Hz,1H), 4.64 (t, J=4.9 Hz, 1H), 4.41 (d, J=14.3 Hz, 1H), 4.01 (dd, J=4.4,14.0 Hz, 1H), 3.87 (s, 3H), 3.50-3.40 (m, 1H).

Example 286(4bS,5R,6S,7S,7aR)-6-(((2,2-difluoroethyl)amino)methyl)-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 286F)

Synthesis of(4bS,5R,6S,7S,7aR)-6-(((2,2-difluoroethyl)amino)methyl)-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (Cpd. No.286F)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 0.650 g, 1.18 mmol) in tetrahydrofuran (10 mL), Borane dimethylsulphide (1.1 mL, 11.8 mmol), was added at 0° C. and stirred the mixturefor 3 h at room temperature. After completion, reaction mixture wasquenched with methanol (5.0 mL) and again heated for 12 h at 80° C. Thereaction mixture was concentrated to give crude product. The crudeproduct was purified by combi-flash (12 g, RediSep column) using 20%methanol in dichloromethane as eluent. The desired fractions wereconcentrated under reduced pressure. The compound was re-purified byreverse phase prep HPLC, desired fractions were lyophilized to giverac-(4bS,5R,6S,7S,7aR)-6-(((2,2-difluoroethyl)amino)methyl)-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diolas white solid. Yield: 365 mg, 57%. The enantiomers were separated bychiral preparative HPLC [Chiralpak IG (4.6×250) mm, 5μ];n-Hexane/EtOH=85/15 (V/V) Peak 1 (Cpd. No. 286F, 19 mg), [α]_(D) −9.3°(c 0.23, CHCl₃), R_(t)=14.7, ee 99.52%; MS (ESI) m/z 537.23 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.98 (s, 1H), 7.39 (s, 4H),7.07-6.98 (m, 5H), 5.83 (t, J=56.8 Hz, 1H), 5.68 (s, 1H), 5.19 (d, J=5.0Hz, 1H), 4.56 (s, 1H), 3.89 (s, 3H), 3.76 (d, J=14.2, 1H), 3.17 (bs,1H), 2.89 (bs, 2H), 2.69 (bs, 2H), 2.03 (bs, 1H). Peak 2 (19 mg),[α]_(D) +90.0° (c 0.26, CHCl₃), R_(t)=20.05, ee:98.48%; MS (ESI) m/z537.22 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.06 (s, 1H), 7.98 (s, 1H),7.39 (s, 4H), 7.05-6.98 (m, 5H), 5.97 (t, J=56.8 Hz, 1H), 5.68 (s, 1H),5.19 (d, J=4.5 Hz, 1H), 4.56 (s, 1H), 3.89 (s, 3H), 3.74 (d, J=14.1,1H), 3.18 (bs, 1H), 2.89 (bs, 2H), 2.69-2.66 (m, 2H), 2.13 (bs, 1H).

Example 287Rac-4-((4bS,5R,7S,7aR)-4b,5-dihydroxy-4-methoxy-5-(morpholinomethyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 287F)

Synthesis ofrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-7,7a-dihydrospiro[cyclopenta[4,5]furo[2,3-c]pyridine-5,2′-oxiran]-4b(6H)-ol(2)

To a solution of trimethylsulfoxonium iodide (0.38 g, 1.76 mmol) indimethyl sulfoxide (2 ml) was added 1.0 M potassium tert-butoxide (1.65ml, 1.65 mmol) in tetrahydrofuran at room temperature and reactionmixture stirred for 1 h. Reaction mixture then cooled to −5° C., andrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-7-phenyl-4b,6,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(1, 0.50 g, 1.10 mmol) in mixture of dimethyl sulfoxide (2 ml) andtetrahydrofuran (2 ml) was added slowly over a period of 5 min. Thereaction mixture then stirred at 0° C. for 2 h. The reaction mixture wasquenched by addition of cold water and extracted with ethyl acetate. Theorganic layer was washed with cold water, brine, dried over anhydroussodium sulphate and concentrated under reduced pressure to get crude.The crude obtained was purified by silica gel (100-200 mesh size) columnchromatography using 2% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-7,7a-dihydrospiro[cyclopenta[4,5]furo[2,3-c]pyridine-5,2′-oxiran]-4b(6H)-ol(2). Yield: 0.17 g, 33%; MS (ESI) m/z 466.10[M+1]⁺.

Synthesis ofrac-(4bS,5R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-5-(morpholinomethyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3)

In a sealed vial a solution of compoundrac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-7,7a-dihydrospiro[cyclopenta[4,5]furo[2,3-c]pyridine-5,2′-oxiran]-4b(6H)-ol(2, 0.1 g, 0.215 mmol), and morpholine (0.092 ml, 1.07 mmol) in ethanolwas heated at 80° C. for 5 h. The reaction mixture was concentratedunder reduced pressure. The crude obtained was triturated with diethylether. The solid obtained was again triturated with pentane and dried toaffordrac-(4bS,5R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-5-(morpholinomethyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3). Yield 0.040 g, 34.0%; MS (ESI) m/z 553.28[M+1]⁺.

Synthesis ofrac-4-((4bS,5R,7S,7aR)-4b,5-dihydroxy-4-methoxy-5-(morpholinomethyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 287F)

To the solution ofrac-(4bS,5R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-5-(morpholinomethyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3, 0.050 g, 0.090 mmol) in N,N-dimethylformamide (3 ml), zinc cyanide(0.064 g, 0.54 mmol) and zinc dust (0.001 g, 0.01 mmol) were added atroom temperature and the reaction mixture was degassed with argon for 15minutes, tris(dibenzylideneacetone)dipalladium (0.0024 g, 0.0027 mmol)and 1,1′-Bis(diphenylphosphino) ferrocene (0.001 g, 0.0018 mmol) wereadded and reaction mixture was heated at 140° C. for 5 h. Aftercompletion, the reaction mixture was diluted with ethyl acetate andwashed with cold water. The organic layer was separated and dried overanhydrous sodium sulphate, filtered and concentrated to give crudeproduct. The crude product was purified by preparative HPLC Afterpurification compound was loaded on Phenomenex (strata-X-C) column andeluted in 5% methanolic ammonia to get purerac-4-((4bS,5R,7S,7aR)-4b,5-dihydroxy-4-methoxy-5-(morpholinomethyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 287F) as a white solid. Yield: 0.01 g, 22%; MS (ESI) m/z500.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 8.16 (s, 1H), 8.05 (s, 1H), 7.52(d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.12-7.03 (m, 5H), 5.57 (s,1H), 5.52 (s, 1H), 3.90 (s, 3H), 3.70 (dd, J=5.6, 14.8 Hz, 1H), 3.49(bs, 4H), 2.93-2.89 (m, 1H), 2.66-2.51 (m, 3H), 2.39-1.90 (m, 4H).

Example 288(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 288F)

Synthesis ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3,3-difluoroazetidin-1-yl)methanone(2)

To a solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 2.0 g, 3.76 mmol) in dichloromethane (20 mL) at 0° C. wereadded 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (2.14 g, 5.64 mmol), andN,N-diisopropylethylamine (4.0 ml, 22.1 mmol), and reaction mixture wasstirred for 5 min. 3,3-difluoroazetidine hydrochloride (1.43 g, 11.2mmol) was then added at the same temperature and the reaction mixturewas stirred for 16 h at room temperature. After completion, the reactionmixture was diluted with dichloromethane and washed with cold water. Theorganic layer was separated and dried over anhydrous sodium sulphate,filtered and concentrated to give crude product. The crude product waspurified by silica gel (100-200 mesh size) column chromatography using0-5% methanol in dichloromethane as eluent. The desired fractions wereconcentrated to affordrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3,3-difluoroazetidin-1-yl)methanone(2) as yellow solid. Yield: 2.00 g, 90%; MS (ESI) m/z 605.10[M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-difluoroazetidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3)

To a solution ofrac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3,3-difluoroazetidin-1-yl)methanone(2, 2.00 g, 3.6 mmol) in dry tetrahydrofuran (20 ml) at 0° C., boranedimethyl sulphide complex (3.5 ml, 36.4 mmol) was added drop wise over aperiod of 5 min. The reaction mixture was slowly brought to roomtemperature and stirred for additional 16 h. After completion, thereaction mass was quenched with methanol at 0° C. and heated to refluxfor 10 h. After completion, solvent was removed under reduced pressureand the residue was purified by silica gel (100-200 mesh size) columnchromatography using 5% methanol in dichloromethane as eluent. Thedesired fractions were concentrated under reduced pressure to affordrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-difluoroazetidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(3) as white solid. Yield: 1.0 g, 51%; MS (ESI) m/z 593.19[M+1]⁺.

Synthesis of(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 288F)

To a solution ofrac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3-difluoroazetidin-1-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (3, 1.0 g, 1.68 mmol) inN,N-dimethylformamide (10 mL), zinc cyanide (1.15 g, 10.1 mmol) and zincdust (0.011 g, 0.168 mmol) were added at room temperature and thereaction mixture was degassed with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.186 g, 0.336 mmol) andtris(dibenzylideneacetone)dipalladium (0.153 g, 0.168 mmol) were addedto the reaction mixture, degassed for additional 5 min and mixture washeated at 130° C. for 2 h. After completion, the reaction mixture wasdiluted with ethyl acetate and washed with cold water. The organic layerwas separated and dried over anhydrous sodium sulphate, filtered andconcentrated to give crude product. The crude product was purified bysilica gel (100-200 mesh size) column chromatography using 2-3% methanolin dichloromethane as eluent. The desired fractions were concentrated toaffordrac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 288F) as white solid. Yield: 0.50 g, MS (ESI) m/z531.23[M+1]⁺. The enantiomers were separated by chiral SFC [CHIRALPAK IA(4.6×250)mm, 5μ]: CO₂/MeOH/TEA(80:20:0.2)]. Peak 1 (160 mg), R_(t)=2.416min, ee: 99.78%, [α]_(D) −89.4° (c 0.25, CHCl₃); MS (ESI) m/z531.23[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 7.56-7.51 (m, 3H), 7.34 (d,J=8.4 Hz, 2H), 7.11-7.07 (m, 2H), 7.01 (d, J=7.6 Hz, 3H), 5.88 (s, 1H),5.42 (s, 1H), 4.46 (s, 1H), 3.89 (s, 3H), 3.79 (d, J=14.0 Hz, 1H), 3.64(bs, 3H), 3.06-2.99 (m, 1H), 2.79-2.74 (m, 1H), 2.58-2.37 (m, 2H).Peak-2 (170 mg), R_(t)=4.573 min, ee: 99.32%, [α]_(D) +71.9° (c 0.35,CHCl₃) MS (ESI) m/z 531.23[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 7.55-7.50(m, 3H), 7.34 (d, J=8.4 Hz, 2H), 7.08-7.07 (m, 2H), 7.01 (d, J=6.8 Hz,3H), 5.87 (s, 1H), 5.42 (s, 1H), 4.46 (s, 1H), 3.89 (s, 3H), 3.79 (d,J=14.0 Hz, 1H), 3.64 (bs, 3H), 3.03-2.98 (m, 1H), 2.80-2.73 (m, 1H),2.58-2.38 (m, 2H).

Example 289Rac-(4bR,7S,7aR)-4-methoxy-5-(morpholinomethyl)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 289F)

Synthesis ofrac-(4bR,7S,7aR)-4b-hydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(2)

To a solution of rac-methyl(4bR,6R,7S,7aR)-4b-hydroxy-4-methoxy-5-oxo-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate(1, 2.0 g, 3.98 mmol) in dimethyl sulphoxide (20 mL), lithium chloride(0.50 g, 11.9 mmol) was added. The reaction mixture was stirred at 150°C. for 15 min. After completion, the reaction mass was cooled to roomtemperature and quenched with cold water. The solid obtained wasfiltered, washed with water and then dissolved in dichloromethane. Thedichloromethane layer was dried over anhydrous sodium sulphate, filteredand concentrated under reduced pressure to get crude product. The crudeproduct was purified by silica gel (100-200 mesh) column chromatographyeluting with dichloromethane to affordrac-(4bR,7S,7aR)-4b-hydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(2) as white solid. Yield: 1.15 g, 75%; MS (ESI) m/z 442.2[M+1]⁺.

Synthesis ofrac-(4bR,7S,7aR,E)-4-methoxy-5-(methoxymethylene)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(4)

To a solution ofrac-(4bR,7S,7aR)-4b-hydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-5-one(2, 1.30 g, 2.94 mmol) in methanol (15 mL) at 0° C. was addeddimethyl(1-diazo-2-oxopropyl)phosphonate (3, 0.84 g, 4.42 mmol) followedby potassium carbonate (0.81 g, 5.88 mmol). The reaction mixture wasstirred at 0° C. for 30 min, then the reaction mixture was stirred atroom temperature for 16 h. After completion, saturated solution ofsodium bicarbonate (30 mL) was added. The precipitated solid wasfiltered, washed with water, n-pentane and dried under vacuum to affordrac-(4bR,7S,7aR,E)-4-methoxy-5-(methoxymethylene)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(4) as white solid. Yield: 1.1 g, 79.7%; MS (ESI) m/z 470.25[M+1]⁺.

Synthesis ofrac-(4bR,7S,7aR)-4b-hydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-5-carbaldehyde(5)

To a solution ofrac-(4bR,7S,7aR,E)-4-methoxy-5-(methoxymethylene)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(4, 1.0 g, 2.13 mmol) in tetrahydrofuran(20 mL) at 0° C. was added 6 Nhydrochloric acid (10 mL). The reaction mixture was stirred for 18 h atroom temperature. After completion, the reaction mass was cooled andneutralized by the addition of saturated sodium bicarbonate up to pH ˜7.and extracted with ethyl acetate, The organic layer was separated anddried over anhydrous sodium sulphate, filtered and concentrated, thecrude product obtained was triturated in n-pentane and filtered off togiverac-(4bR,7S,7aR)-4b-hydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-5-carbaldehyde(5) as pale yellow solid. Yield: 0.62 g, 64%; MS (ESI) r/z 454.26[M−1]⁻.

Synthesis ofrac-(4bR,5R,7S,7aR)-4-methoxy-5-(morpholinomethyl)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 289F)

To a solution ofrac-(4bR,7S,7aR)-4b-hydroxy-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-5-carbaldehyde(5, 0.61 g, 1.34 mmol) in methanol (20 mL) at 0° C., morpholine (0.68mL, 6.7 mmol) and acetic acid (catalytic) was added. The reactionmixture was stirred for 18 h at room temperature. Then sodiumborohydride (0.05 g, 1.34 mmol) was added at 0° C. and reaction mixturewas stirred for another 3 h at room temperature. After completion, thereaction mixture was quenched with ice water and extracted withdichloromethane. The organic layer was separated and dried overanhydrous sodium sulphate, filtered and concentrated to give crudeproduct. The crude product was purified by preparative HPLC to affordrac-(4bR,5R,7S,7aR)-4-methoxy-5-(morpholinomethyl)-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol(Cpd. No. 289F) as white solid. Yield: 10 mg, 1.4%; MS (ESI) m/z527.27[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) 8.17 (s, 1H), 8.07 (s, 1H), 7.47(d, J=8.36 Hz, 2H), 7.40 (d, J=8.20 Hz, 2H), 7.07-6.95 (m, 5H), 5.70 (s,1H), 3.96 (m, 4H), 3.80-3.52 (m, 6H), 3.08-2.58 (m, 5H), 2.28 (m, 2H).

Example 2904-((4bS,5R,6S,7S,7aR)-6-((tert-butylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 290F)

Synthesis ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(tert-butyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(2)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylicacid (1, 5.0 g, 10.0 mmol) in N,N-dimethylformamide (50 mL) at 0° C.,2-methylpropan-2-amine (6.0 g, 50.0 mmol), N,N-diisopropylethylamine(11.0 mL, 60.0 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (5.70 g, 30.0 mmol) and 1-Hydroxybenzotriazole (4.50 g,30.0 mmol) were added and reaction mixture was stirred for 16 h at roomtemperature. After completion, the reaction mixture was diluted with icecold water to obtain solid. This solid was filtered off and the cake wasdissolved in 10% methanol in dichloromethane. The organic layer wasdried over anhydrous sodium sulphate, filtered and concentrated to givecrude. The crude was purified by column chromatography using silica gel(100-200 mesh) and 0-4% methanol in dichloromethane as eluent. Thedesired fractions were concentrated to affordrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(tert-butyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(2) as white solid. Yield: 1.80 g, 32%; MS (ESI) m/z 553.41[M+1]⁺.

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((tert-butylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(tert-butyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(2, 1.8 g, 3.20 mmol) in dry tetrahydrofuran (20 mL) at 0° C., boranedimethyl sulphide complex (4.50 mL, 48.0 mmol) was added drop wise andreaction mixture was stirred at room temperature 16 h. After completion,the reaction mass was quenched with methanol at 0° C. and heated toreflux for 6 h. After completion, solvent was removed under reducedpressure to give crude which was purified by column chromatography usingsilica gel (100-200 mesh) and 0-15% methanol in dichloromethane aseluent. The desired fractions were concentrated under reduced pressureto affordrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((tert-butylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3) as white solid. Yield: 1.40 g, 82.3%; MS (ESI) m/z 539.45 [M+1]⁺.

Synthesis of4-((4bS,5R,6S,7S,7aR)-6-((tert-butylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 290F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-6-((tert-butylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3, 1.40 g, 2.50 mmol) in N,N-dimethylformamide (20.0 mL), zinc cyanide(1.70 g, 15.0 mmol) and zinc dust (0.081 g, 1.25 mmol) were added andthe reaction mixture was degassed under argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.114 g, 0.125 mmol) andtris(dibenzylideneacetone)dipalladium (0.14 g, 0.25 mmol) were added tothe reaction, degassed for additional 5 min and mixture was heated at140° C. for 16 h. After completion, the reaction mass was diluted icecold water and extracted with ethyl acetate. The organic layer waswashed with water, dried over anhydrous sodium sulphate, filtered andconcentrated to give crude which was purified by column chromatographyusing silica gel (100-200 mesh) and 0-15% methanol in dichloromethane aseluent. The desired fractions were concentrated to affordrac-4-((4bS,5R,6S,7S,7aR)-6-((tert-butylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrileas white solid. Yield: 0.820 g, 65% (racemic); MS (ESI) m/z 486.49[M+1]⁺. The enantiomers were separated by chiral SFC [chiralpak IG(4.6×150) mm, 5μ], CO2/0.1% TEA in EtOH=(60/40) Peak 1 (Cpd. No. 290F,55 mg), [α]_(D) −34.2° (c 0.25, CHCl₃), R_(t)=1.73 min, ee: 99.9%; MS(ESI) m/z 486.36[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) 8.05 (s, 1H), 7.97 (s,1H), 7.48 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.09-7.05 (m, 2H),7.00-6.98 (m, 3H), 5.76 (s, 1H), 5.65 (s, 1H), 4.54 (s, 1H), 3.88 (s,3H), 3.85 (s, 1H), 3.05-3.01 (m, 1H), 2.62-2.57 (m, 2H), 1.57-1.52 (s,1H), 0.98 (s, 9H). Peak-2 (58 mg) [α]_(D) +28.5° (c 0.27, CHCl₃),R_(t)=2.42 min, ee: 99.88%; MS (ESI) m/z 486.32[M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) 8.05 (s, 1H), 7.97 (s, 1H), 7.49 (d, J=8.44 Hz, 2H), 7.35 (d,J=8.5 Hz, 2H), 7.09-7.05 (m, 2H), 7.00-6.98 (m, 3H), 5.77 (s, 1H), 5.66(s, 1H), 4.54 (s, 1H), 3.88 (s, 3H), 3.85 (s, 1H), 3.15-3.10 (m, 1H),2.62-2.56 (m, 2H), 1.64 (s, 1H), 0.94 (s, 9H).

Example 2914-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(((2,2,2-trifluoroethyl)amino)methyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 291F)

Synthesis ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(((2,2,2-trifluoroethyl)amino)methyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3)

To a solution ofrac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-N-(2,2,2-trifluoroethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide(1, 1.20 g, 1.9 mmol) in tetrahydrofuran (20 mL), borane dimethylsulphide (1.90 mL, 19.0 mmol) was added at 0° C. and mixture was stirredat 60° C. for 3 h. After completion, reaction mass was quenched withmethanol (10.0 mL) and again heated for 16 h at 60° C. The reactionmixture was concentrated to giverac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(((2,2,2-trifluoroethyl)amino)methyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3) as off white solid. Yield: 1.0 g, 85%; MS (ESI) m/z 565.1[M+1]⁺

Synthesis of4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(((2,2,2-trifluoroethyl)amino)methyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 291F)

To a solution ofrac-(4bS,5R,6S,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-(((2,2,2-trifluoroethyl)amino)methyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(3, 1.0 g, 1.7 mmol) in N,N-dimethylformamide (15.0 mL), zinc cyanide(1.24 g, 10.6 mmol) and zinc (0.115 g, 1.7 mmol) were added at roomtemperature and degassed the mixture with argon for 15 min.1,1′-Bis(diphenylphosphino)ferrocene (0.029 g, 0.05 mmol),tris(dibenzylideneacetone)dipalladium (0.048 g, 0.05 mmol) were added tothe reaction and degassing was continued for another 5 min. The reactionmixture was heated at 140° C. for 16 h. After completion, the reactionwas cooled to room temperature and passed through celite bed. Thefiltrate was diluted with ethyl acetate and washed with water. Theorganic layer was separated, dried over anhydrous sodium sulphate andconcentrated under reduced pressure to give the crude. The crude waspurified by combi-flash (4.0 g, RediSep column) using 30-70% ethylacetate in hexane as eluent. The desired fractions were concentratedunder reduced pressure. The compound was again re-purified by reversephase prep and desired fractions were lyophilized to giverac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(((2,2,2-trifluoroethyl)amino)methyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 291F) as white solid. Yield: 513 mg, 56%. The enantiomers wereseparated by chiral SFC [Chiralpak IG (4.6×250)mm, 5μ]; CO₂/0.1% TEA inEtOH=(60/40); Peak 1 (108 mg), [α]_(D) +29.5° (c 0.26, CHCl₃),R_(t)=1.84, ee>99%; MS (ESI) m/z 512.27 [M+1]⁺; UPLC: 98.7%; 1H NMR (400MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.98 (s, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.37(d, J=8.1 Hz, 2H), 7.08-6.97 (m, 5H), 5.71 (s, 1H), 5.14 (d, J=5.6 Hz,1H), 4.54 (t, J=4.7 Hz, 1H), 3.89 (s, 3H), 3.73 (d, J=14.1 Hz, 1H),3.27-3.14 (m, 3H), 2.75-2.70 (m, 1H), 2.39 (bs, 1H). Peak 2 (117 mg),[α]_(D) −30.7° (c 0.27, CHCl₃), R_(t)=2.23, ee>95%; MS (ESI) m/z 512.27[M+1]⁺; UPLC: 95.7%; 1H NMR (400 MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.98 (s,1H), 7.50 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.08-6.97 (m, 5H),5.71 (s, 1H), 5.14 (d, J=5.6 Hz, 1H), 4.54 (t, J=4.8 Hz, 1H), 3.89 (s,3H), 3.73 (d, J=14.1 Hz, 1H), 3.27-3.14 (m, 3H), 2.75-2.70 (m, 1H), 2.38(bs, 1H).

Example 292Rac-(5aR,6S,7S,8R,8aS)-7-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 292F)

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(2)

To a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (1, 0.1 g, 0.18 mmol) in N,N-dimethylformamide (1 mL) was addedHATU (69.77 mg, 0.18300 mmol) and then DIPEA (0.15 mL, 0.87000 mmol).After 1 hr LCMS (taken in methanol) indicated complete consumption ofthe SM, so ammonium chloride was added in one portion. The reaction wasallowed to stir for an additional 65 hr, at which point the mixture waspoured onto water and diluted with ethyl acetate. The organic materialwas washed with sat ammonium chloride, water, and brine, then dried overmagnesium sulfate, filtered, and solvent removed in vacuum to affordrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(2). This material was carried on to the subsequent step without furtherpurification. LCMS (ESI) m/z 531.1, 533.1 [M+1]⁺.

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-7-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 292F)

To a stirred solution ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide(2, 0.09 g, 0.16300 mmol) in THF (2.5 mL) was added boranedimethylsulfide (0.84 mL, 1.68 mmol) dropwise. After 3.5 hr the reactionwas cooled to rt and MeOH (1 mL) was added slowly with vigorousevolution of gas. The reaction was then heated to 60° C. and monitoredby LCMS. 20 hr after the addition of methanol, the vial was cooled to rtand solvent removed in vacuo. The residue was taken up in a mixture ofdichloromethane and methanol, then purified on strata ion exchangecolumn, washing first with acetonitrile and MeOH (twice with each), theneluting the product with several washes with a solution of 5% NH₄OH, 20%dichloromethane, and 75% MeOH. The solvent was removed in vacuo, and theresidue was taken up in a mixture of water and acetonitrile. Thissolution was frozen and lyophilized to affordrac-(5aR,6S,7S,8R,8aS)-7-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 292F) as a white solid. Yield: 69 mg, 81%. LCMS (ESI) m/z517.1, 519.1 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.21 (d, J=8.6 Hz, 2H),7.10-7.00 (m, 4H), 6.99 (d, J=7.0 Hz, 1H), 6.93 (d, J=7.3 Hz, 2H), 6.84(s, 1H), 5.48 (s, 1H), 4.50 (s, 1H), 3.63 (d, J=14.4 Hz, 1H), 2.95 (s,2H), 2.59 (d, J=9.8 Hz, 1H), 2.52 (dd, J=12.7, 3.5 Hz, 1H).

Example 293Rac-(5aR,6S,7S,8R,8aS)-7-(aminomethyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 293F)

Synthesis ofrac-(5aR,6S,7S,8R,8aS)-7-(aminomethyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 293F)

Rac-(5aR,6S,7S,8R,8aS)-7-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 0.03 g, 0.056 mmol), dicyanozinc (46 mg, 0.39 mmol), dppf (31 mg,0.056 mmol) and zinc (4 mg, 0.056 mmol) in N,N-dimethylformamide (0.56mL) and 0.056 mL water. Tris(dibenzylideneacetone)dipalladium(0) (22 mg,0.024 mmol) was added, the vial was sealed and stirred at 120° C. After45 min LCMS indicated the product and chlorocyano product were majorcomponents. The mixture was cooled to rt after 1 h, diluted withmethanol and a few drops of DMSO then filtered through celite. The padwas washed several times with methanol containing a small amount ofDMSO. The volatile solvents were removed in vacuo, the residue wasdiluted with DMSO and purified via RP-HPLC to affordrac-(5aR,6S,7S,8R,8aS)-7-(aminomethyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 293F). Yield: 6.0 mg, 23%. LCMS (ESI) m/z 455.1 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 7.58 (s, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.27 (d,J=8.5 Hz, 2H), 7.13-7.01 (m, 4H), 7.00-6.91 (m, 4H), 6.49 (s, 1H), 5.32(s, 1H), 4.68-4.55 (m, 1H), 3.89 (s, 2H), 3.83-3.73 (m, 1H), 2.90 (s,1H).

Example 294Rac-4-((5aR,6S,7S,8R,8aS)-7-(aminomethyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 294F)

Synthesis ofrac-4-((5aR,6S,7S,8R,8aS)-7-(aminomethyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 294F)

Rac-(5aR,6S,7S,8R,8aS)-7-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(1, 0.03 g, 0.056 mmol), dicyanozinc (46 mg, 0.39 mmol), dppf (31 mg,0.056 mmol) and zinc (4 mg, 0.056 mmol) in N,N-dimethylformamide (0.56mL) and water (0.056 mL). Tris(dibenzylideneacetone)dipalladium(0) (22mg, 0.024 mmol) was added, the vial was sealed and stirred at 120° C.After 45 min LCMS indicated the product and bis-cyanated product weremajor components. The mixture was cooled to room temperature after 1 h,diluted with methanol and a few drops of DMSO then filtered throughcelite. The pad was washed several times with methanol containing asmall amount of DMSO. The volatile solvents were removed in vacuo, theresidue was diluted with DMSO and purified via RP-HPLC to affordrac-4-((5aR,6S,7S,8R,8aS)-7-(aminomethyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 294F). Yield: 7.5 mg, 28%. LCMS (ESI) m/z 464.2, 466.4 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 7.55 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.6 Hz,2H), 7.06 (dq, J=13.4, 7.1 Hz, 4H), 7.00-6.89 (m, 2H), 6.49 (s, 1H),5.23 (s, 1H), 4.61-4.52 (m, 1H), 3.83 (s, 3H), 3.79 (d, J=14.5 Hz, 1H),2.91 (bs, 1H).

Example 295Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (Cpd. No. 295F)

Synthesis ofrac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (Cpd. No. 295F)

To a stirred solution of rac-methyl(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate(1, 1.09 g, 1.99 mmol) in methanol (40 mL) was added water (4 mL) andthen lithium hydroxide (477 mg, 19.9 mmol). The resulting yellowreaction mixture was stirred vigorously and heated at 50° C. under areflux condenser for 4.5 h. The reaction mixture was cooled with a 0° C.cold bath and 1 N hydrochloric acid in water (19.9 mL, 19.9 mmol) wasadded with vigorous stirring. A few more drops of 1 N hydrochloric acidwas added to make the mixture slightly acidic. Most of the methanol wasremoved on a rotary evaporator. The residue was extracted three timeswith dichloromethane. The combined organics were washed with brine,dried over magnesium sulfate, filtered, concentrated on a rotaryevaporator, and dried under high vacuum at 40° C. overnight to affordcruderac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylicacid (Cpd. No. 295F) as a white solid. Yield: 961 mg, 90%; MS (ESI) m/z532.1, 534.0[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H), 7.24-7.18(m, 2H), 7.06 (m, 2H), 7.03-6.94 (m, 5H), 6.93 (s, 1H), 5.62 (d, J=8.3Hz, 2H), 4.62 (t, J=5.3 Hz, 1H), 4.29 (d, J=13.9 Hz, 1H), 3.95 (dd,J=14.0, 5.0 Hz, 1H), 3.84 (s, 3H).

Example 296

The following compounds, denoted below as compounds A through DQ, can besynthesized by one of skill in the art according to the proceduresprovided in the indicated general methods (“GM”) and/or the individualexamples (“EXP”). The compounds contain substituents Ra, Rb and Rc,which are defined in Table 1. For example, the first compound below isCompound A, and it can be made from the appropriate starting materialsaccording to the procedures described in general method (“GM”) 3 or GM3.

Compounds A-DQ

TABLE 1 Ra Rb Rc Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

Cl Cl

Cl CN

Cl CF₂H

Cl CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

CN CF₃

CN Cl

CN CN

CN CF₂H

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Example 297 Cell Proliferation

Human tumor cell lines were cultured in the appropriate media (DMEM andRPMI) supplemented with penicillin G (100 U/ml), streptomycin (100μg/ml), 10% FBS in a humidified atmosphere of 5% CO₂ maintained at 37°C. Exponentially growing cells were seeded at 2,500 cells/well in 96well plates prior to drug treatment. The following day, cells weretreated with either DMSO (vehicle control) or eIF4A inhibitors at theappropriate dose for 72 hours at 37° C. Following compound treatment,cell proliferation was assessed by CellTiter-Glo assay (Promega, MadisonWis.) according to the manufacturer's protocol. Dose-response curveswere fitted by non-linear regression (sigmoidal dose response model)using KaleidaGraph (Synergy Software, Reading Pa.) and IC₅₀ values werecalculated.

The results of these assays with MDA-MB-231 human breast cancer cellsare set forth in Table 2 below. To this end, IC₅₀ values of less than100 nM are labelled as “+++”, from 100 nM to 1000 nM are labelled as“++”, and greater than 1000 nM are labelled as “+” (NA means “notavailable”).

TABLE 2 MDA-MB-231 cell proliferation assay (IC₅₀) Cpd. Cpd. No. IC₅₀No. IC₅₀  1F ++  2F ++  3F +++  4F ++  5F ++  6F ++  7F ++  8F ++  9F + 10F +  11F ++  12F +  13F +  14F ++  15F +  16F ++  17F ++  18F +++ 19F ++  20F +++  21F +  22F ++  23F +  24F +  25F +  26F ++  27F ++ 28F ++  29F +  30F ++  31F +  32F +  33Fa ++  33Fb +  34F +  35F + 36F +  37F +  38F +  39F ++  40Fa NA  40Fb ++  40Fc NA  41Fa +  41Fb ++ 41Fc +  42F ++  43F +  44F +  45F +  46F +  47F +  48F +  49F ++  50F++  51F ++  52F ++  53F +++  54F ++  55F ++  56F +  57F +  58F +  59F + 60F +  61F +  62F ++  63F +  64F +++  65F ++  66F +++  67F ++  68F ++ 69F ++  70F ++  71F +++  72F ++  73F +++  74F +++  75F ++  76F +++  77F+++  78F ++  79F +  80F +  81F +++  82F +  83F +++  84F +  85F +  86F + 87F +++  88F +++  89F +++  90F +++  91F +  92F +  93F +  94F +  95F ++ 96F +  97F ++  98F ++  99F + 100F + 101F ++ 102F ++ 103F +++ 104F ++105F + 106F ++ 107F ++ 108F ++ 109F ++ 110F ++ 111F +++ 112F ++ 113F ++114F +++ 115F ++ 116F +++ 117F + 118F ++ 119F ++ 120F +++ 121F ++ 122F++ 123F ++ 124F ++ 125F + 126F ++ 127F ++ 128F ++ 129F + 130F + 131F +132F + 133F + 134F NA 135F +++ 136F +++ 137F +++ 138F +++ 139F +++ 140F+++ 141F ++ 142F +++ 143F +++ 144F +++ 145F +++ 146F +++ 147F +++ 148F +149F + 150F +++ 151F +++ 152F +++ 153F ++ 154F ++ 155F ++ 156Fa +++156Fb +++ 156Fc +++ 157Fa ++ 157Fb ++ 157Fc ++ 158Fa +++ 158Fb +++ 158Fc+++ 159Fa +++ 159Fb +++ 159Fc +++ 160Fa ++ 160Fb + 161F + 162F ++ 163F++ 164F ++ 165F ++ 166F ++ 167F ++ 168F + 169F + 170F +++ 171F ++ 172F+++ 173F +++ 174F +++ 175F +++ 176F ++ 177F ++ 178F +++ 179F +++ 180F+++ 181F +++ 182F +++ 183F +++ 184F +++ 185F +++ 186F +++ 187F +++ 188F+++ 189F ++ 190F ++ 191F ++ 192F + 193F ++ 194F + 195F ++ 196F +++ 197F++ 198Fa +++ 198Fb +++ 199F +++ 200F +++ 201 +++ 202F +++ 203F +++ 204F+++ 205F +++ 206F +++ 207Fa ++ 207Fb ++ 208Fa ++ 208Fb ++ 209F +++ 210F+++ 211Fa +++ 211Fb +++ 212F +++ 213F +++ 214F ++ 215F +++ 216F +++ 217F+++ 218F +++ 219F +++ 220F +++ 221F +++ 222F +++ 223F NA 224F +++ 225F+++ 226F +++ 227F + 228F + 229F +++ 230F +++ 231F +++ 232F +++ 233F ++234F + 235F +++ 236F ++ 237F +++ 238F ++ 239F +++ 240F ++ 241F +++ 242F++ 243F ++ 244F +++ 245F ++ 246F ++ 247F +++ 248F +++ 249F +++ 250F +251F +++ 252F +++ 253F +++ 254F +++ 255F ++ 256F +++ 257F +++ 256F +++257F +++ 258F +++ 259F ++ 260F +++ 261F +++ 262F +++ 263F +++ 264F +++265F ++ 266F +++ 267F ++ 268F ++ 269F +++ 270F ++ 271F ++ 272F +++ 273F+++ 274F ++ 275F +++ 276F ++ 277F +++ 278F ++ 279F +++ 280F ++ 281F ++282F ++ 283F ++ 284F ++ 285F ++ 286F ++ 287F + 288F +++ 289F ++ 290F ++291F ++ 292F +++ 293F +++ 294F +++ 295F +++

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet areincorporated herein by reference, in their entirety. Aspects of theembodiments can be modified, if necessary to employ concepts of thevarious patents, applications and publications to provide yet furtherembodiments.

These and other changes can be made to the embodiments in light of theabove-detailed description. In general, in the following claims, theterms used should not be construed to limit the claims to the specificembodiments disclosed in the specification and the claims, but should beconstrued to include all possible embodiments along with the full scopeof equivalents to which such claims are entitled.

1. A compound according to Formula (I):

or stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, wherein: X is CR⁶R⁷, O, S, NH, N(C₁-C₈)alkyl, C(O), C═CR⁶R⁷,N(CO)R⁸, S(O) or S(O)₂; Y is a 5-membered heteroaryl or a 6-memberedaryl or heteroaryl; R¹ and R² independently are aryl, heterocyclyl,heteroaryl or cycloalkyl; R^(3a), R^(3b), R^(4a) and R^(4b)independently are H, halogen, CN, C₁-C₈(alkyl), (C₁-C₈)haloalkyl,C₂-C₈(alkenyl), (C₂-C₈)alkynyl, OR⁹, NHR⁹, NR⁹R⁹, [(C₁-C₈)alkylene]OR⁹,[(C₁-C₈)alkylene]NHR⁹, [(C₁-C₈)alkylene]NR⁹R⁹, C(O)R⁸, C(O)NHR⁹,C(O)NR⁹R⁹, C(O)[(C₁-C₈)alkylene]NHR⁹, C(O)[(C₁-C₈)alkylene]NR⁹R⁹, CO₂R⁹,C(S)NHR⁹, C(S)NR⁹R⁹, SR⁹, S(O)R⁹, SO₂R⁹, SO₂NHR⁹, SO₂NR⁹R⁹, NH(CO)R⁸,NR⁹(CO)R⁸, NH(CO)NHR⁹, NH(CO)NR⁹R⁹, NR⁹(CO)NHR⁹, NR⁹(CO)NR⁹R⁹,P(O)(OH)(OR⁹), P(O)(OR⁹) (OR⁹), aryl, heteroaryl, cycloalkyl orheterocyclyl; R^(3a) and R^(3b), and R^(4a) and R^(4b) independentlycombine to form oxo or alkenyl, or a cycloalkyl or heterocyclyl ring; orR^(3a) and R^(4a), R^(3b) and R^(4b) or R^(4a) and R⁵ together with thecarbon atom to which they are attached form a cycloalkyl or heterocyclylring; or R² and R^(3a) together with the carbon atom to which they areattached form a bicyclic ring system; R⁵ is H, halogen, OH, CN, N₃, SR⁹,(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl,(C₂-C₈)alkynyl, NHC(O)(C₁-C₈)alkyl or heteroaryl; R⁶ and R⁷independently are H, CN, halogen, OR⁹, SR⁹, (C₁-C₈)alkyl, NH(R⁹) orNR⁹R⁹; R⁸ is H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, O(C₁-C₈)alkyl,O(C₁-C₈)haloalkyl, cycloalkyl, O(cycloalkyl), heterocyclyl,O(heterocyclyl), aryl, O(aryl), heteroaryl or O(heteroaryl); R⁹ is H,(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, cycloalkyl, heterocyclyl,[(C₁-C₈)alkylene]heterocyclyl, aryl, [(C₁-C₈)alkylene]aryl orheteroaryl; wherein the two R⁹'s together with the nitrogen atom towhich they are attached of NR⁹R⁹, [(C₁-C₈)alkylene]NR⁹R⁹, C(O)NR⁹R⁹,C(O)[(C₁-C₈)alkylene]NR⁹R⁹, C(S)NR⁹R⁹, SO₂NR⁹R⁹, NH(CO)NR⁹R⁹ orNR⁹(CO)NR⁹R⁹, optionally form a heterocyclyl ring; wherein any alkyl,alkenyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionallysubstituted with 1, 2, or 3 groups selected from OH, CN, SH, SO₂NH₂,SO₂(C₁-C₄)alkyl, SO₂NH(C₁-C₄)alkyl, halogen, NH₂, NH(C₁-C₄)alkyl,N[(C₁-C₄)alkyl]₂, C(O)NH₂, COOH, COOMe, acetyl, (C₁-C₈)alkyl,O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, NH₂—C(O)-alkylene,NH(Me)-C(O)-alkylene, CH₂—C(O)-lower alkyl, C(O)-lower alkyl,alkylcarbonylaminyl, CH₂—[CH(OH)]_(m)—(CH₂)_(p)—OH,CH₂—[CH(OH)]_(m)—(CH₂)_(p)-NH₂ or CH₂-aryl-alkoxy; or wherein any alkyl,cycloalkyl or heterocyclyl is optionally substituted with oxo; “m” and“p” are 1, 2, 3, 4, 5 or 6; and wherein when Y is a 6-membered aryl thenX is not O.
 2. The compound according to claim 1 wherein X is O.
 3. Thecompound according to claim 1 wherein the 6-membered aryl or heteroarylis

wherein A¹ is N or CR¹⁰; A² is N or CR¹¹; A³ is N or CR¹²; A⁴ is N orCR¹³; and R¹⁰, R¹¹, R¹² and R¹³ independently are H, halogen,C₁-C₈(alkyl), (C₁-C₈)haloalkyl, C(O)O(C₁-C₈)alkyl, C(O)(C₁-C₈)alkyl,SO₂(C₁-C₈)alkyl, C₁-C₈(alkenyl), (C₁-C₈)alkynyl, OR⁹, NHR⁹, NR⁹R⁹, CN,[(C₁-C₈)alkylene]OR⁹, [(C₁-C₈)alkylene]NHR⁹, [(C₁-C₈)alkylene]NR⁹R⁹,C(O)R⁸, C(O)NHR⁹, C(O)NR⁹R⁹, C(O)[(C₁-C₈)alkylene]NHR⁹,C(O)[(C₁-C₈)alkylene]NR⁹R⁹, CO₂R⁹, C(S)NHR⁹, C(S)NR⁹R⁹, SR⁹, S(O)R⁹,SO₂R⁹, SO₂N(H)(R⁹), SO₂NR⁹R⁹, NH(CO)R⁸, NR⁹(CO)R⁸, NH(CO)NHR⁹,NH(CO)NR⁹R⁹, NR⁹(CO)NHR⁹, NR⁹(CO)NR⁹R⁹, P(O)(OH)(OR⁹), P(O)(OR⁹) (OR⁹),aryl, heteroaryl, cycloalkyl, or heterocyclyl.
 4. The compound accordingto claim 1 wherein A² and A⁴ are N, A¹ is CR¹⁰ and A³ is CR¹², whereinR¹⁰ and R¹² independently are H, CN, halogen or OR⁹; A² is N, A¹ isCR¹⁰, A³ is CR¹² and A⁴ is CR¹³, wherein R¹⁰, R¹² and R¹³ independentlyare H, CN, halogen or OR⁹; A³ is N, A¹ is CR¹⁰, A² is CR¹¹ and A⁴ isCR¹³, wherein R¹⁰, R¹ and R¹³ independently are H, CN, halogen or OR⁹;or A⁴ is N, A¹ is CR¹⁰, A² is CR¹¹ and A³ is CR¹², wherein R¹⁰, R¹¹ andR¹² independently are H, CN, halogen or OR⁹.
 5. The compound accordingto claim 4 wherein A² is N, A¹ is CR¹⁰, A³ is CR¹² and A⁴ is CR¹³wherein R¹⁰, R¹² and R¹³ independently are H, CN, halogen or OR⁹; or A³is N, A¹ is CR¹⁰, A² is CR¹¹ and A⁴ is CR¹³, wherein R¹⁰, R¹¹ and R¹³independently are H, CN, halogen or OR⁹.
 6. The compound according toclaim 1 wherein R¹ and R² are aryl.
 7. The compound according to claim 1wherein R^(3a), R^(3b), R^(4a) and R^(4b) independently are H, halogen,C₁-C₈(alkyl), (C₁-C₈)haloalkyl, OH, CN, [(C₁-C₈)alkylene]OR⁹,[(C₁-C₈)alkylene]NHR⁹, [(C₁-C₈)alkylene]NR⁹R⁹, C(O)NH₂, C(O)NHR⁹,C(O)NR⁹R⁹, C(O)R⁹, CO₂R⁹, C(S)NH₂, S(O)R⁹, SO₂R⁹, SO₂NHR⁹, SO₂NR⁹R⁹,heteroaryl or cycloalkyl, wherein R⁹ is a C₁-C₈(alkyl) or(C₁-C₈)haloalkyl, or wherein the two R⁹'s together with the nitrogenatom to which they are attached of [(C₁-C₈)alkylene]NR⁹R⁹, C(O)NR⁹R⁹ orSO₂NR⁹R⁹, optionally form a heterocyclyl ring.
 8. The compound accordingto claim 1 wherein R^(3b) is [(C₁-C₈)alkylene]NHR⁹ or[(C₁-C₈)alkylene]NR⁹R⁹, wherein R⁹ is C₁-C₈(alkyl) or (C₁-C₈)haloalkyl,or wherein the two R⁹'s together with the nitrogen atom to which theyare attached of [(C₁-C₈)alkylene]NR⁹R⁹ optionally form a heterocyclylring.
 9. The compound according to claim 8 wherein R^(3b) is[(C₁-C₈)alkylene]NR⁹R⁹ and R⁹ is C₁-C₈(alkyl).
 10. The compoundaccording to claim 1 wherein R^(4b) is OH.
 11. The compound according toclaim 1 wherein R⁵ is OH.
 12. The compound according to claim 1 whereinR⁶ and R⁷ are H or C₁-C₈(alkyl).
 13. The compound according to claim 1wherein R⁹ is H or C₁-C₈(alkyl).
 14. The compound according to claim 1selected from(5aR,6S,7S,8R,8aS)-7-((Dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 147F),4-((5aR,6S,7S,8R,8aS)-3-Chloro-8,8a-dihydroxy-1-methoxy-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 198aF),(5aR,6S,7S,8R,8aS)-7-(Azetidin-1-ylmethyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 212F),(5aR,6S,7S,8R,8aS)-5a-(4-Chlorophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxyxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 145F),Rac-(5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 144F),Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 143F),Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol(Cpd. No. 142F),Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 196F),(5aR,6S,7S,8R,8aS)-5a-(4-Cyanophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 139F),Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 207bF),Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 152F),Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 157bF),Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 158bF),4-((5aR,6S,7S,8R,8aS)-7-((Dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 231F),Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 159bF),4-((5aR,6S,7S,8R,8aS)-3-Chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile(Cpd. No. 140F),Rac-(5aR,6S,7S,8R,8aS)-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 146F),(5aR,6S,7S,8R,8aS)-5a-(4-Cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 151F),Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 197F),Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 207aF),Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 157cF),Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoropyrrolidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 153F),Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 159cF),Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-5a,7,8,8a-tetrahydro-6H-cyopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile(Cpd. No. 158cF),Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-(morpholino-methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 180F),Rac-4-((4bR,5R,6R,7S,7aR)-5-((dimethylamino)methyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 206F),4-((4bS,5R,6S,7S,7aR)-6-((Dimethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile(Cpd. No. 66F),(4bS,5R,6S,7S,7aR)-7a-(4-Chlorophenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 272F),(4bS,5R,6S,7S,7aR)-7a-(4-(Difluoromethyl)phenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 106F), and(4bS,5R,6S,7S,7aR)-6-((Dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol(Cpd. No. 107F).
 15. A pharmaceutical composition comprising (i) atherapeutically effective amount of at least one compound according toclaim 1 or a stereoisomer, a tautomer or a pharmaceutically acceptablesalt thereof; (ii) in combination with a pharmaceutically acceptablecarrier, diluent or excipient.
 16. A method for treating a eIF4Adependent condition in a mammal in need thereof comprising administeringto the mammal (i) a therapeutically effective amount of at least onecompound according to claim 1 or a stereoisomer, tautomer orpharmaceutically acceptable salt thereof, or (ii) a pharmaceuticalcomposition of claim
 15. 17. The method according to claim 16 whereinthe eIF4A dependent condition is a disease of uncontrolled cell growth,proliferation and/or survival, or is a disease of inappropriate cellularinflammatory responses.
 18. The method according to claim 17 wherein theeIF4A dependent condition is cancer.
 19. The method of claim 17 whereinthe eIF4A dependent condition is a solid tumor, colorectal cancer,bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, headand neck cancer, brain cancer, malignant glioma, fibrotic diseases,glioblastoma, hepatocellular cancers, thyroid cancer, lung cancer,non-small cell lung cancer, small cell lung cancer, melanoma, multiplemelanoma, myeloma, pancreatic cancer, pancreatic carcinoma, renal cellcarcinoma, renal cancer, cervical cancer, urothelial cancer, prostatecancer, castration-resistant prostate cancer, ovarian cancer, breastcancer, triple-negative breast cancer, leukemia, acute myeloid leukemia,Hodgkins lymphoma, non-Hodgkins lymphoma, B-cell lymphoma, T-celllymphoma, hairy cell lymphoma, diffuse large B-cell lymphoma, Burkitt'slymphoma, multiple myeloma, myelodysplastic syndrome, Alzheimer's,Parkinson's, Fragile X Syndrome and autism disorders.
 20. The method ofclaim 19 wherein the eIF4A dependent condition is diffuse large B-celllymphoma, hepatocellular cancers, acute myeloid leukemia, breast cancer,colorectal cancer, small cell lung cancer and non-small cell lungcancer.